Section 3 Hypoglycemia

*Blood Glucose Levels*

in oxidative muscle of swimming rats. Frontiers in Physiology. 2016;**7**:132

[21] Jae SY, Kurl S, Laukkanen JA, Zaccardi F, Choi YH, Fernhall B, Carnethon M, Franklin BA. Exercise heart rate reserve and recovery as predictors of incident type 2 diabetes. American Journal of Medicine.

[22] Terziotti P, Schena F, Gulli G, Cevese A. Post-exercise recovery of autonomic cardiovascular control: A study by spectrum and cross-spectrum analysis in humans. European Journal of Applied Physiology. 2001;**84**:187-194

[23] Guasch E, Benito B, Qi X, et al. Atrial fibrillation promotion by

of Cardiology. 2013;**62**(1):68-77

[24] Kuo YR, Wang CT, Wang FS, Chiang YC, Wang CJ. Extracorporeal shock-wave therapy enhanced wound healing via increasing topical blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes. Wound Repair and Regeneration.

2009;**17**(4):522-530

endurance exercise: Demonstration and mechanistic exploration in an animal model. Journal of the American College

2016;**129**(5):536

[15] Polito MD, Farinatti PTV. Respostas de frequência cardíaca, pressão arterial e duplo-produto ao exercício contraresistência: uma revisão da literatura. Revista Portuguesa de Ciências do

[16] Chiu CY, Yang RS, Sheu ML, Chan DC, Yang TH, Tsai KS, Chiang CK, Liu SH. Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-downregulated, Akt pathway. The Journal of Pathology. 2016;**238**(3):470-482

[17] Nikooie R, Rajabi H, Gharakhanlu R, Atabi F, Omidfar K, Aveseh M, Larijani B. Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ. Journal of Physiology and Biochemistry. 2013;**69**:865-877

[18] Silva MJ, Brodt MD, Lynch MA, McKenzie JA, Tanouye KM, Nyman JS, Wang X. Type 1 diabetes in young rats leads to progressive trabecular bone loss, cessation of cortical bone growth, and diminished whole bone strength and fatigue life. Journal of Bone and Mineral

Research. 2009;**24**(9):1618-1627

[19] Freeman JV, Dewey FE, Hadley DM, Myers J, Froelicher VF. Autonomic nervous system interaction with the cardiovascular system during exercise. Progress in Cardiovascular Diseases. Mar–Apr 2006;**48**(5):342-362

[20] Yilmaz OH, Karakulak UN, Tutkun E, Bal C, Gunduzoz M, ErcanOnay E, Ayturk M, TekOzturk M, Alaguney ME. Assessment of cardiac autonomic nervous system in mercury exposed individuals via post-exercise heart rate recovery. Medical Principles and Practice. 2016;**25**(4):343-349. DOI:

Desporto. 2003;**3**(1):79-91

**64**

10.1159/000445322

**67**

**Chapter 5**

**Abstract**

**1. Introduction**

Hypoglycemia

Carbohydrate Metabolism in

*María L. Kennedy and Miguel A. Campuzano-Bublitz*

Hypoglycemia is generated by mechanisms directly related to an increase in insulin secretion, by metabolic disorders that require increased glucose consumption or by a deficient metabolic production of glucose by the body. Mechanisms include high glucose intake, increased dose of oral hypoglycemic, exogenous administration of insulin, metabolic hepatic conditions that lead to an increase in the production of amino acids, growing tumors, and in diabetic pregnant woman with abnormal increase in glucose and amino acids that end up producing insulin hypersecretion in the newborn. Work that requires high glucose expenditure or reduction of insulin antagonist, such as cortisol and glucagon, ends up in hypoglycemia. Finally, hypoglycemia is generated by metabolic deficit in pathophysiological situations such as defects in enzymatic systems, alcoholic hepatitis, and insufficient nutrition. The most characteristic symptoms include bulimia, fits of sweating, and tremors due to a strong activation of the sympathetic system. Obviously, the CNS is strongly affected by the lack of glucose, which is even more complicated because also hypoglycemia leads to a situation of decreased lipolysis and ketone bodies that finally seriously compromise the supply of energy to the nervous system, producing losses of consciousness, spasms, and even irreversible brain damage.

**Keywords:** hypoglycemia, increased glucose consumption, hyperinsulinemia, exogenous insulin control, uncontrolled diabetes, high glucose expenditure

The human body is dependent on a tight control of its blood glucose levels to ensure normal body function. Survival of individuals, the conscious state, the integration of different types of internal and external stimuli, and appropriate responses to these stimuli depend on the proper functioning of the central nervous system, which puts intense activity in their cells. This requires the consumption of oxygen and glucose to obtain the energy that enables the activity of the central

The lack of oxygen causes, in minutes, serious and irreparable damage to the central nervous system. However, the lack of glucose is tolerated for a longer time because in a deficit situation, the CNS itself makes autonomous adjustments leading to inactivity to other non-vital systems of the body and preserves for more time the availability of glucose for neurons, and ultimately, in multiday starvation states, it substitutes glucose for ketone bodies as a nutrient, which allows life expectancy to be extended during fasting. The availability of glucose in people is vital for a good quality of life, since it allows the lucid and full functioning of the CNS [2, 3].

The rest of the body's cells also obtain energy through oxygen and glucose, thus enabling metabolism and cellular response. The main source of glucose is through

nervous system (CNS) and keeps the neurons in constant activity [1].

#### **Chapter 5**

## Carbohydrate Metabolism in Hypoglycemia

*María L. Kennedy and Miguel A. Campuzano-Bublitz*

#### **Abstract**

Hypoglycemia is generated by mechanisms directly related to an increase in insulin secretion, by metabolic disorders that require increased glucose consumption or by a deficient metabolic production of glucose by the body. Mechanisms include high glucose intake, increased dose of oral hypoglycemic, exogenous administration of insulin, metabolic hepatic conditions that lead to an increase in the production of amino acids, growing tumors, and in diabetic pregnant woman with abnormal increase in glucose and amino acids that end up producing insulin hypersecretion in the newborn. Work that requires high glucose expenditure or reduction of insulin antagonist, such as cortisol and glucagon, ends up in hypoglycemia. Finally, hypoglycemia is generated by metabolic deficit in pathophysiological situations such as defects in enzymatic systems, alcoholic hepatitis, and insufficient nutrition. The most characteristic symptoms include bulimia, fits of sweating, and tremors due to a strong activation of the sympathetic system. Obviously, the CNS is strongly affected by the lack of glucose, which is even more complicated because also hypoglycemia leads to a situation of decreased lipolysis and ketone bodies that finally seriously compromise the supply of energy to the nervous system, producing losses of consciousness, spasms, and even irreversible brain damage.

**Keywords:** hypoglycemia, increased glucose consumption, hyperinsulinemia, exogenous insulin control, uncontrolled diabetes, high glucose expenditure

#### **1. Introduction**

The human body is dependent on a tight control of its blood glucose levels to ensure normal body function. Survival of individuals, the conscious state, the integration of different types of internal and external stimuli, and appropriate responses to these stimuli depend on the proper functioning of the central nervous system, which puts intense activity in their cells. This requires the consumption of oxygen and glucose to obtain the energy that enables the activity of the central nervous system (CNS) and keeps the neurons in constant activity [1].

The lack of oxygen causes, in minutes, serious and irreparable damage to the central nervous system. However, the lack of glucose is tolerated for a longer time because in a deficit situation, the CNS itself makes autonomous adjustments leading to inactivity to other non-vital systems of the body and preserves for more time the availability of glucose for neurons, and ultimately, in multiday starvation states, it substitutes glucose for ketone bodies as a nutrient, which allows life expectancy to be extended during fasting. The availability of glucose in people is vital for a good quality of life, since it allows the lucid and full functioning of the CNS [2, 3].

The rest of the body's cells also obtain energy through oxygen and glucose, thus enabling metabolism and cellular response. The main source of glucose is through

food and specifically depends on the consumption of carbohydrates [4]. The use of this carbohydrate in the body is finely regulated by a hormonal system capable of always maintaining blood glucose (glycemia) in a concentration ranging from 4.0 to 5.4 mmol/L (72 to 99 mg/dL) [5]. The human body is prepared to store excess of glucose (glycogenesis) and use it in the future (glycogenolysis) when this is required and is also able to synthesize glucose from noncarbohydrate precursors (substrates) such as amino acids, lactate, and/or glycerol (gluconeogenesis).

The pancreas is the body in charge, among other functions, of maintaining glycemia at tolerable levels for the organism, through a system of hormones, where insulin is responsible for reducing glycemia in situations of postprandial hyperglycemia, while glucagon is responsible for reversing situations of hypoglycemia [6, 7].

#### **2. Carbohydrate metabolism**

The carbohydrates present in foods are primarily as polysaccharides that are digested by various digestive enzymes. Starch is the most common polysaccharide in foods and is metabolized to maltose by the enzyme alpha amylase present in saliva and secreted by the pancreas and this to glucose by the maltases in the microvilli of the duodenum. The lactose present in dairy products is metabolized by lactases in the intestinal villi to glucose and galactose. Sucrose is also metabolized in the intestinal microvilli in glucose and fructose.

The absorption of glucose and galactose is carried out by a secondary active cotransport of Na+ to the interior of the enterocyte and from there to the portal flow by facilitated diffusion through the GLUT2 glucose transporter (**Figure 1**). Fructose, on the other hand, is only entered into the enterocyte by facilitated diffusion through GLUT5 type transporters located on the apical side, and then they are poured into the portal circulation by the same carrier proteins that are also found on the basal side of the enterocyte.

The duodenum has a very extensive contact surface, in order to take advantage of and absorb as much of these nutrients as possible. The excess, which passes to the jejunum, stimulates the release of the glucose-dependent insulinotropic peptide (GIP) from the K cells and the glucagon-like peptide type 1 (GLP-1) from the L cells. Both stimulate the postprandial release of insulin from the pancreas (**Figure 1**).

Absorbed glucose increases suddenly in the blood, reaching values above 90 mg/dL, and is transported by the GLUT2 carrier protein inside the pancreas where it undergoes glycolysis to generate pyruvate. This is used by the mitochondria for the production of ATP, which is released into the cytoplasm of the beta cells of the pancreas. This excess of ATP desensitizes the ATP-dependent K+ channels that close and prevent the migration of K+ ions to the extracellular fluid. With the intracellular increase of K+ , a depolarization begins; this stimulates the opening of voltage-gated calcium channels, which finally ends with the exocytosis of insulin (**Figure 1**), peptide C, and amylin stored in the vesicles into the bloodstream.

The average life of this circulating insulin is 3–5 minutes; its main action is to stimulate the uptake of glucose from the bloodstream, mainly by the liver and muscle cells. The receptor for insulin in these cells is a tyrosine kinase that, when insulin binds, dimerizes and initiates a signaling cascade that rapidly activates the phosphatidylinositol-3-kinase (PI3K) pathway that translocates GLUT4 carrier to the cell membrane, which allows the massive entry of glucose into the cell. Then the same pathway activates the enzyme glycogen synthetase that converts excess of glucose into glycogen, activates Acetyl CoA carboxylase that stimulates lipogenesis, and finally, in the longer term, activates the pathway of the mitogen-activated kinases (MAP kinases) responsible for the expression of the protein synthesis (**Figure 1**).

**69**

**Figure 1.**

*pyruvate and then ATP; ATP closes K+*

C peptide is a small molecule that is released when proinsulin is metabolized to insulin; in spite of not knowing the specific physiological role of this molecule, in the clinical environment, it serves to correlate it with the quantity of insulin synthesized by beta cells, because for each molecule of insulin, there is a C peptide, and this remains in the bloodstream for a longer time. Amylin, a peptide hormone produced in the pancreas, and co-secreted with insulin, and in the brain, improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion. Amylin

*Carbohydrate metabolism. Polysaccharides in food are digested, by several enzymes. The absorption is mainly in the duodenum. Glucose in the jejunum and ileum stimulates the release of GIP and GLP-1, and postprandial release of insulin is stimulated. Glucose in blood reaches the pancreas and undergoes glycolysis to generate* 

*channels are open and exocytosis of insulin occurs. Insulin binds to its tyrosine kinase receptor and initiates a* 

*signaling cascade that rapidly produces the massive entry of glucose into the cell.*

 *channels, and a depolarization begins. Next, voltage-gated calcium* 

also acts centrally as a satiation signal, reducing food intake and body weight.

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362* *Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

*Blood Glucose Levels*

**2. Carbohydrate metabolism**

the basal side of the enterocyte.

and prevent the migration of K+

increase of K+

cotransport of Na+

the intestinal microvilli in glucose and fructose.

food and specifically depends on the consumption of carbohydrates [4]. The use of this carbohydrate in the body is finely regulated by a hormonal system capable of always maintaining blood glucose (glycemia) in a concentration ranging from 4.0 to 5.4 mmol/L (72 to 99 mg/dL) [5]. The human body is prepared to store excess of glucose (glycogenesis) and use it in the future (glycogenolysis) when this is required and is also able to synthesize glucose from noncarbohydrate precursors (substrates) such as amino acids, lactate, and/or glycerol (gluconeogenesis). The pancreas is the body in charge, among other functions, of maintaining glycemia at tolerable levels for the organism, through a system of hormones, where insulin is responsible for reducing glycemia in situations of postprandial hyperglycemia, while glucagon is responsible for reversing situations of hypoglycemia [6, 7].

The carbohydrates present in foods are primarily as polysaccharides that are digested by various digestive enzymes. Starch is the most common polysaccharide in foods and is metabolized to maltose by the enzyme alpha amylase present in saliva and secreted by the pancreas and this to glucose by the maltases in the microvilli of the duodenum. The lactose present in dairy products is metabolized by lactases in the intestinal villi to glucose and galactose. Sucrose is also metabolized in

The absorption of glucose and galactose is carried out by a secondary active

flow by facilitated diffusion through the GLUT2 glucose transporter (**Figure 1**). Fructose, on the other hand, is only entered into the enterocyte by facilitated diffusion through GLUT5 type transporters located on the apical side, and then they are poured into the portal circulation by the same carrier proteins that are also found on

The duodenum has a very extensive contact surface, in order to take advantage of and absorb as much of these nutrients as possible. The excess, which passes to the jejunum, stimulates the release of the glucose-dependent insulinotropic peptide (GIP) from the K cells and the glucagon-like peptide type 1 (GLP-1) from the L cells. Both stimulate the postprandial release of insulin from the pancreas (**Figure 1**).

Absorbed glucose increases suddenly in the blood, reaching values above 90 mg/dL,

, a depolarization begins; this stimulates the opening of voltage-gated

channels that close

ions to the extracellular fluid. With the intracellular

and is transported by the GLUT2 carrier protein inside the pancreas where it undergoes glycolysis to generate pyruvate. This is used by the mitochondria for the production of ATP, which is released into the cytoplasm of the beta cells of the

calcium channels, which finally ends with the exocytosis of insulin (**Figure 1**),

The average life of this circulating insulin is 3–5 minutes; its main action is to stimulate the uptake of glucose from the bloodstream, mainly by the liver and muscle cells. The receptor for insulin in these cells is a tyrosine kinase that, when insulin binds, dimerizes and initiates a signaling cascade that rapidly activates the phosphatidylinositol-3-kinase (PI3K) pathway that translocates GLUT4 carrier to the cell membrane, which allows the massive entry of glucose into the cell. Then the same pathway activates the enzyme glycogen synthetase that converts excess of glucose into glycogen, activates Acetyl CoA carboxylase that stimulates lipogenesis, and finally, in the longer term, activates the pathway of the mitogen-activated kinases (MAP kinases) responsible for the expression of the protein synthesis (**Figure 1**).

pancreas. This excess of ATP desensitizes the ATP-dependent K+

peptide C, and amylin stored in the vesicles into the bloodstream.

to the interior of the enterocyte and from there to the portal

**68**

#### **Figure 1.**

*Carbohydrate metabolism. Polysaccharides in food are digested, by several enzymes. The absorption is mainly in the duodenum. Glucose in the jejunum and ileum stimulates the release of GIP and GLP-1, and postprandial release of insulin is stimulated. Glucose in blood reaches the pancreas and undergoes glycolysis to generate pyruvate and then ATP; ATP closes K+ channels, and a depolarization begins. Next, voltage-gated calcium channels are open and exocytosis of insulin occurs. Insulin binds to its tyrosine kinase receptor and initiates a signaling cascade that rapidly produces the massive entry of glucose into the cell.*

C peptide is a small molecule that is released when proinsulin is metabolized to insulin; in spite of not knowing the specific physiological role of this molecule, in the clinical environment, it serves to correlate it with the quantity of insulin synthesized by beta cells, because for each molecule of insulin, there is a C peptide, and this remains in the bloodstream for a longer time. Amylin, a peptide hormone produced in the pancreas, and co-secreted with insulin, and in the brain, improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion. Amylin also acts centrally as a satiation signal, reducing food intake and body weight.

In this way the glycemia values are usually maintained between 70 and 110 mg/dL; values below this range produce hypoglycemia that stimulates the release of the hormone glucagon from the alpha cells of the pancreas, which promotes anti-insulin effects in such a way to re-raise the glycemia values (**Figure 2**). To this is added a third pancreatic hormone, somatostatin, of paracrine regulation which collaborates to modulate the release of insulin and glucagon.

#### **Figure 2.**

*Regulation of plasma glucose level by insulin and glucagon. Hypoglycemia situations related to diabetes and not related to diabetes.*

**71**

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

that reinforces the effect of glycogenolysis [10].

blood and therefore a decrease in blood sugar (**Figure 2**).

**4. Nondiabetic hypoglycemia**

hypoglycemia (**Figure 2**).

esis are drastically reduced (**Figure 2**).

hypoglycemia [6, 8, 9].

**3. Glucagon**

cal range.

After intense physical activity, the adrenaline released by the stimulus of exercise and the increase of lactate and pyruvate in blood blocks insulin secretion and stimulates glucagon to always make glucose available to the body and avoid reactive

Insulin secretion from the beta cells of the pancreas is a standard response that is directly related to glucose absorbed from food. Thus, if the glycemia increases significantly after an intake, this results in a large insulin secretion, while if the glycemia remains within the normal range, the stimulus decreases and produces a pulsatile insulin secretion that favors the glycemia to remain within the physiologi-

In the case that the glycemia falls below 60 mg/dL, the signal to secrete insulin weakens and eventually becomes blocked. In contrast, this allows the alpha cells of the pancreas to release considerable amounts of glucagon (**Figure 2**). This hormone travels through the portal vein to the liver, where it activates signaling pathways to initiate glycogenolysis, which will cause the formation of glucose in the liver so that it is released into the bloodstream to immediately increase glycemia. Additionally, glucagon increases the recruitment of amino acids to the liver for gluconeogenesis

Hypoglycemia is almost always related to a normal or increased amount of insulin as a direct response to glucose intake in food or other pathophysiological factors that induce an excessive increase in insulin secretion. A balanced intake of carbohydrates, fats, and proteins provides all the nutrients that the body needs for survival, but an inadequate diet, deficient in carbohydrates, leads to a reactive hypoglycemia. The chronic and excessive intake of alcohol produces metabolic alterations in the liver that lead to decrease the synthesis and release of glucose from the liver to the

In the case that the gastric emptying is accelerated (dumping syndrome), due for example, to a gastric resection, the digestion and absorption of carbohydrates are much faster than normal and also produce the early release of intestinal hormones, including the GIP, which leads to hyperinsulinemia and then the consequent

The alteration of various functions of the organism has as one of its consequences the reduction of glycemia to critical values, as occurs in the reduction of glucocorticoid secretion, such as cortisol, which causes an increase in glycolysis and reduced gluconeogenesis from amino acids. This in turn leads to a greater secretion of adrenaline that is contrasted in its effects to insulin. On the other hand, thyroid hormones regulate many cellular metabolic processes, including hepatic metabolism; therefore, in a situation of hypothyroidism, glycogenolysis and gluconeogen-

An alteration in the hepatic metabolism of amino acids, either due to liver failure or due to specific enzymatic defects, such as that inducing high leucine level, has an effect on insulin secretion, which is increased producing hypoglycemia (**Figure 2**). Hepatomegaly is usually caused by an increased hepatic storage of glycogen, known as glycogenosis, due to metabolic alterations produced by defective enzymes such as glucose-6-phosphatase, in Gierke's disease, or a debranching enzyme in Cori

After intense physical activity, the adrenaline released by the stimulus of exercise and the increase of lactate and pyruvate in blood blocks insulin secretion and stimulates glucagon to always make glucose available to the body and avoid reactive hypoglycemia [6, 8, 9].

#### **3. Glucagon**

*Blood Glucose Levels*

**70**

**Figure 2.**

*related to diabetes.*

*Regulation of plasma glucose level by insulin and glucagon. Hypoglycemia situations related to diabetes and not* 

In this way the glycemia values are usually maintained between 70 and 110 mg/dL;

values below this range produce hypoglycemia that stimulates the release of the hormone glucagon from the alpha cells of the pancreas, which promotes anti-insulin effects in such a way to re-raise the glycemia values (**Figure 2**). To this is added a third pancreatic hormone, somatostatin, of paracrine regulation which collaborates

to modulate the release of insulin and glucagon.

Insulin secretion from the beta cells of the pancreas is a standard response that is directly related to glucose absorbed from food. Thus, if the glycemia increases significantly after an intake, this results in a large insulin secretion, while if the glycemia remains within the normal range, the stimulus decreases and produces a pulsatile insulin secretion that favors the glycemia to remain within the physiological range.

In the case that the glycemia falls below 60 mg/dL, the signal to secrete insulin weakens and eventually becomes blocked. In contrast, this allows the alpha cells of the pancreas to release considerable amounts of glucagon (**Figure 2**). This hormone travels through the portal vein to the liver, where it activates signaling pathways to initiate glycogenolysis, which will cause the formation of glucose in the liver so that it is released into the bloodstream to immediately increase glycemia. Additionally, glucagon increases the recruitment of amino acids to the liver for gluconeogenesis that reinforces the effect of glycogenolysis [10].

#### **4. Nondiabetic hypoglycemia**

Hypoglycemia is almost always related to a normal or increased amount of insulin as a direct response to glucose intake in food or other pathophysiological factors that induce an excessive increase in insulin secretion. A balanced intake of carbohydrates, fats, and proteins provides all the nutrients that the body needs for survival, but an inadequate diet, deficient in carbohydrates, leads to a reactive hypoglycemia.

The chronic and excessive intake of alcohol produces metabolic alterations in the liver that lead to decrease the synthesis and release of glucose from the liver to the blood and therefore a decrease in blood sugar (**Figure 2**).

In the case that the gastric emptying is accelerated (dumping syndrome), due for example, to a gastric resection, the digestion and absorption of carbohydrates are much faster than normal and also produce the early release of intestinal hormones, including the GIP, which leads to hyperinsulinemia and then the consequent hypoglycemia (**Figure 2**).

The alteration of various functions of the organism has as one of its consequences the reduction of glycemia to critical values, as occurs in the reduction of glucocorticoid secretion, such as cortisol, which causes an increase in glycolysis and reduced gluconeogenesis from amino acids. This in turn leads to a greater secretion of adrenaline that is contrasted in its effects to insulin. On the other hand, thyroid hormones regulate many cellular metabolic processes, including hepatic metabolism; therefore, in a situation of hypothyroidism, glycogenolysis and gluconeogenesis are drastically reduced (**Figure 2**).

An alteration in the hepatic metabolism of amino acids, either due to liver failure or due to specific enzymatic defects, such as that inducing high leucine level, has an effect on insulin secretion, which is increased producing hypoglycemia (**Figure 2**).

Hepatomegaly is usually caused by an increased hepatic storage of glycogen, known as glycogenosis, due to metabolic alterations produced by defective enzymes such as glucose-6-phosphatase, in Gierke's disease, or a debranching enzyme in Cori Forbes disease, a phosphorylase in Hers disease, or a phosphoryl kinase in Huijing's disease. This increase in hepatic glycogen deposition produces a marked hypoglycemia throughout the system (**Figure 2**).

Aberrations in the expression of certain genes in beta cells make them unable to relate the increase in lactate and pyruvate with the state of physical activity and therefore induce an increase in insulin secretion that causes significant hypoglycemia in the organism (**Figure 2**).

The development of tumors, of any type, entails an increase in the need for energetic molecules so that cell proliferation is possible. This added to the fact that the formation of tumors produces long-term hormonal disorders that keep oncological patients with hypoglycemia for a long time. This effect is compensated by lipolysis of the adipocytes in order to make more energetic molecules available, and finally the patient develops tumor cachexia [11, 12] (**Figure 2**).

#### **5. Hypoglycemia related to diabetes**

One of the most common causes of hypoglycemia in diabetics occurs as a result of the excess administration of insulin or oral hypoglycemic drugs [13, 14]. Patients suffering from diabetes mellitus type 1 and whose treatment is based on the exogenous administration of insulin must previously corroborate the level of glycemia and then adjust the amount of hormone to be administered, considering that 100% of the dose, approximately half, is used to immediately regulate the metabolism of carbohydrates and the other half is to cover the metabolism at night or fasting hours. Therefore, the amount of insulin administered is higher than required, and if the necessary precautions are not taken, there is a high probability that the dose administered will produce a strong hypoglycemia, especially during sleep hours, known as the Somogyi effect. The amount of insulin units to administer considers the actual value of the glycemia, which forces the patient to measure it, compare and extract the difference with the theoretical optimum value of 120 mg/dL of fasting blood glucose, and divide it by the factor 50, since one unit of insulin reduces blood glucose by approximately 50 mg/dL (**Figure 2**).

Even so, the correct amount of insulin to be administered must also be defined by other factors, such as the total amount of carbohydrates ingested with food, the type of insulin to be administered, and the recommendations of the treating medical professional.

Oral hypoglycemic agents, used in the treatment of type 2 diabetes mellitus, can also lead to a strong insulin secretion. The large family of sulfonylureas (chlorpropamide, glibenclamide, gliclazide, glisentide, glipizide, gliquidone, and glimepiride) and the secretagogue glinides (repaglinide and nateglinide) are characterized by the ability to induce hypoglycemia and cause weight gain, due to the decrease in the lipolysis in the patients who use it for their treatment (**Figure 2**).

Another interaction with a high probability of producing hypoglycemia is the concomitant treatment with incretin analogues (exenatide) and inhibitors of dipeptidyl peptidases (vildagliptin) because it significantly increases the pancreatic β cell mass, which leads to greater insulin secretion and even with high risks of producing pancreatitis (**Figure 2**).

Diabetic women during pregnancy have poor control of carbohydrate metabolism and thus coexist with high blood levels of glucose and amino acids; this long-term hyperglycemia is transferred to the fetus and forces hyperplasia in fetal pancreatic beta-cell tissue, which finally predisposes the newborn to a greater secretion of insulin and the consequent hypoglycemia [15–17] (**Figure 2**).

**73**

**Figure 3.**

cemia (**Figure 3**).

**7. Treatment of hypoglycemia**

*A summary of glycemia levels and clinical consequences.*

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

The decrease in blood sugar below 60 mg/dL is known as hypoglycemia. In a first phase, this leads to a stimulation of the parasympathetic autonomic nervous system that causes a sensation of hunger and leads the patient to bulimia. In the second phase, the sympathetic autonomic nervous system is stimulated, producing the secretion of important quantities of catecholamines that activate their receptors in important target organs such as the heart, which produces an acceleration of the heartbeat, in sweat glands increases the production of sweat, and in the somatic nervous system causes tremors. It is frequent double vision, difficulty concentrating, loss of ease of speech, and confusion states. A hypoglycemia below 20 mg/dL

The most serious effect is a marked cognitive dysfunction, since the supplies of nutrients, glucose, and ketones to the nervous system are markedly diminished; produce loss of consciousness, brain spasms, and epileptic seizures in children; and

The treatment will depend on the degree of hypoglycemia that the patient develops. That, which does not pass the first phase of the clinical manifestation, requires rapid replacement of glucose from food. The CNS itself is the one that predisposes to this action by triggering bulimia in the patient. Most of the foods available to patients contain abundant amounts of carbohydrates that help to remedy hypogly-

can potentially lead to irreversible neuronal damage [18, 19].

**6. Clinical manifestations**

induces a coma (**Figure 3**).

### **6. Clinical manifestations**

*Blood Glucose Levels*

mia throughout the system (**Figure 2**).

**5. Hypoglycemia related to diabetes**

mia in the organism (**Figure 2**).

Forbes disease, a phosphorylase in Hers disease, or a phosphoryl kinase in Huijing's disease. This increase in hepatic glycogen deposition produces a marked hypoglyce-

Aberrations in the expression of certain genes in beta cells make them unable to relate the increase in lactate and pyruvate with the state of physical activity and therefore induce an increase in insulin secretion that causes significant hypoglyce-

The development of tumors, of any type, entails an increase in the need for energetic molecules so that cell proliferation is possible. This added to the fact that the formation of tumors produces long-term hormonal disorders that keep oncological patients with hypoglycemia for a long time. This effect is compensated by lipolysis of the adipocytes in order to make more energetic molecules available, and

One of the most common causes of hypoglycemia in diabetics occurs as a result of the excess administration of insulin or oral hypoglycemic drugs [13, 14]. Patients suffering from diabetes mellitus type 1 and whose treatment is based on the exogenous administration of insulin must previously corroborate the level of glycemia and then adjust the amount of hormone to be administered, considering that 100% of the dose, approximately half, is used to immediately regulate the metabolism of carbohydrates and the other half is to cover the metabolism at night or fasting hours. Therefore, the amount of insulin administered is higher than required, and if the necessary precautions are not taken, there is a high probability that the dose administered will produce a strong hypoglycemia, especially during sleep hours, known as the Somogyi effect. The amount of insulin units to administer considers the actual value of the glycemia, which forces the patient to measure it, compare and extract the difference with the theoretical optimum value of 120 mg/dL of fasting blood glucose, and divide it by the factor 50, since one unit of insulin reduces

Even so, the correct amount of insulin to be administered must also be defined by other factors, such as the total amount of carbohydrates ingested with food, the type of insulin to be administered, and the recommendations of the treating medi-

Oral hypoglycemic agents, used in the treatment of type 2 diabetes mellitus, can also lead to a strong insulin secretion. The large family of sulfonylureas (chlorpropamide, glibenclamide, gliclazide, glisentide, glipizide, gliquidone, and glimepiride) and the secretagogue glinides (repaglinide and nateglinide) are characterized by the ability to induce hypoglycemia and cause weight gain, due to the decrease in the

Another interaction with a high probability of producing hypoglycemia is the concomitant treatment with incretin analogues (exenatide) and inhibitors of dipeptidyl peptidases (vildagliptin) because it significantly increases the pancreatic β cell mass, which leads to greater insulin secretion and even with high risks of producing

Diabetic women during pregnancy have poor control of carbohydrate metabo-

lism and thus coexist with high blood levels of glucose and amino acids; this long-term hyperglycemia is transferred to the fetus and forces hyperplasia in fetal pancreatic beta-cell tissue, which finally predisposes the newborn to a greater secre-

tion of insulin and the consequent hypoglycemia [15–17] (**Figure 2**).

finally the patient develops tumor cachexia [11, 12] (**Figure 2**).

blood glucose by approximately 50 mg/dL (**Figure 2**).

lipolysis in the patients who use it for their treatment (**Figure 2**).

**72**

cal professional.

pancreatitis (**Figure 2**).

The decrease in blood sugar below 60 mg/dL is known as hypoglycemia. In a first phase, this leads to a stimulation of the parasympathetic autonomic nervous system that causes a sensation of hunger and leads the patient to bulimia. In the second phase, the sympathetic autonomic nervous system is stimulated, producing the secretion of important quantities of catecholamines that activate their receptors in important target organs such as the heart, which produces an acceleration of the heartbeat, in sweat glands increases the production of sweat, and in the somatic nervous system causes tremors. It is frequent double vision, difficulty concentrating, loss of ease of speech, and confusion states. A hypoglycemia below 20 mg/dL induces a coma (**Figure 3**).

The most serious effect is a marked cognitive dysfunction, since the supplies of nutrients, glucose, and ketones to the nervous system are markedly diminished; produce loss of consciousness, brain spasms, and epileptic seizures in children; and can potentially lead to irreversible neuronal damage [18, 19].


**Figure 3.**

*A summary of glycemia levels and clinical consequences.*

### **7. Treatment of hypoglycemia**

The treatment will depend on the degree of hypoglycemia that the patient develops. That, which does not pass the first phase of the clinical manifestation, requires rapid replacement of glucose from food. The CNS itself is the one that predisposes to this action by triggering bulimia in the patient. Most of the foods available to patients contain abundant amounts of carbohydrates that help to remedy hypoglycemia (**Figure 3**).

In cases where hypoglycemia is more pronounced, it is necessary to administer pharmaceutical preparations containing glucose, but this treatment should be monitored to avoid the opposite effect, i.e., hyperglycemia, especially in diabetic patients who triggered hypoglycemia due to excess insulin.

In patients with severe hypoglycemia crisis, which affects the conscience, it is necessary to act urgently administering parenteral glucagon preparations, or glucose will be administered directly, and the rapid recovery of the patient will be monitored [14, 15, 19–21] (**Figure 3**).

#### **8. Conclusion**

Hypoglycemia is generated by mechanisms directly related to an increase in insulin secretion or by metabolic disorders that require increased glucose consumption or by a deficient metabolic production of glucose by the body.

Hyperinsulinemia can be produced by various mechanisms, including high glucose intake in foods, an increased dose of oral hypoglycemic agents, as well as exogenous insulin administration without control, liver metabolic conditions that lead to an increase in the production of amino acids by this organ, tumors in permanent growth, and an abnormal increase in glucose and amino acids in the case of uncontrolled diabetic pregnant women that end up producing insulin hypersecretion in the newborn.

Work that requires high glucose consumption, more than what the body can supply, ends up in situations of hypoglycemia, as well as when there is a decrease in hormone antagonists to insulin, such as cortisol or glucagon. The state of hypoglycemia is generated by metabolic deficit in pathophysiological situations such as defects in enzymatic systems, alcoholic hepatitis, and insufficient diet.

The most characteristic symptoms include bulimia, fits of sweating, and tremors due to a strong activation of the sympathetic system. Primarily, the CNS is strongly affected by the lack of glucose, which is even more complicated because also hypoglycemia leads to a situation of decreased lipolysis and ketone bodies that finally seriously compromise the supply of energy to the central nervous system, producing loss of consciousness, spasms, and even irreversible brain damage.

The treatment of less severe hypoglycemic patients is preferably carried out with the rapid administration of carbohydrate-rich foods. For more serious cases, the use of pharmaceutical products that supply carbohydrates is resorted to, but the glycemia must be monitored to avoid hyperglycemia. Those patients who are much compromised, with loss of consciousness, should receive parenteral glucagon or glucose in an urgent way to recover them.

#### **Conflict of interest**

The authors declare that there is no conflict of interest regarding the publication of this chapter.

**75**

**Author details**

Asunción, San Lorenzo, Paraguay

provided the original work is properly cited.

María L. Kennedy\* and Miguel A. Campuzano-Bublitz\*

Department of Pharmacology, Faculty of Chemical Sciences, National University of

\*Address all correspondence to: lukenrol@qui.una.py and mbublitz@qui.una.py

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362* *Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

*Blood Glucose Levels*

**8. Conclusion**

cretion in the newborn.

In cases where hypoglycemia is more pronounced, it is necessary to administer pharmaceutical preparations containing glucose, but this treatment should be monitored to avoid the opposite effect, i.e., hyperglycemia, especially in diabetic

In patients with severe hypoglycemia crisis, which affects the conscience, it is necessary to act urgently administering parenteral glucagon preparations, or glucose will be administered directly, and the rapid recovery of the patient will be

Hypoglycemia is generated by mechanisms directly related to an increase in insulin secretion or by metabolic disorders that require increased glucose consump-

Hyperinsulinemia can be produced by various mechanisms, including high glucose intake in foods, an increased dose of oral hypoglycemic agents, as well as exogenous insulin administration without control, liver metabolic conditions that lead to an increase in the production of amino acids by this organ, tumors in permanent growth, and an abnormal increase in glucose and amino acids in the case of uncontrolled diabetic pregnant women that end up producing insulin hyperse-

Work that requires high glucose consumption, more than what the body can supply, ends up in situations of hypoglycemia, as well as when there is a decrease in hormone antagonists to insulin, such as cortisol or glucagon. The state of hypoglycemia is generated by metabolic deficit in pathophysiological situations such as

The most characteristic symptoms include bulimia, fits of sweating, and tremors due to a strong activation of the sympathetic system. Primarily, the CNS is strongly affected by the lack of glucose, which is even more complicated because also hypoglycemia leads to a situation of decreased lipolysis and ketone bodies that finally seriously compromise the supply of energy to the central nervous system, produc-

The treatment of less severe hypoglycemic patients is preferably carried out with the rapid administration of carbohydrate-rich foods. For more serious cases, the use of pharmaceutical products that supply carbohydrates is resorted to, but the glycemia must be monitored to avoid hyperglycemia. Those patients who are much compromised, with loss of consciousness, should receive parenteral glucagon or

The authors declare that there is no conflict of interest regarding the publication

defects in enzymatic systems, alcoholic hepatitis, and insufficient diet.

ing loss of consciousness, spasms, and even irreversible brain damage.

glucose in an urgent way to recover them.

**Conflict of interest**

of this chapter.

tion or by a deficient metabolic production of glucose by the body.

patients who triggered hypoglycemia due to excess insulin.

monitored [14, 15, 19–21] (**Figure 3**).

**74**

#### **Author details**

María L. Kennedy\* and Miguel A. Campuzano-Bublitz\* Department of Pharmacology, Faculty of Chemical Sciences, National University of Asunción, San Lorenzo, Paraguay

\*Address all correspondence to: lukenrol@qui.una.py and mbublitz@qui.una.py

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. Journal of Cerebral Blood Flow and Metabolism. 2012;**32**:1222-1232

[2] Rich L, Brown AM. Glycogen: Multiple roles in the CNS. The Neuroscientist. 2017;**23**(4):356-363

[3] Mergenthaler P, Lindauer U, Dienel G, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends in Neurosciences. 2013;**36**(10):587-597

[4] Slavin J, Carlson J. American society for nutrition. Advances in Nutrition. 2014;**5**:760-761

[5] Güemes M, Rahman S, Hussain K. What is a normal blood glucose? Archives of Disease in Childhood. 2015;**0**:1-6

[6] Röder P, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Experimental & Molecular Medicine. 2016;**48**:e219

[7] Hill N, Oliver N, Choudhary P, Levy J, Hindmarsh P, Matthews D. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technology & Therapeutics. 2011;**13**(9):921-928

[8] Dashty M. A quick look at biochemistry: Carbohydrate metabolism. Clinical Biochemistry. 2013;**46**:1339-1352

[9] Slavin J, Carlson J. Carbohydrates. Advances in Nutrition. 2014;**5**:760-761

[10] Briant L, Salehi A, Vergari E, Zhang Q, Rorsman P. Glucagon secretion from pancreatic a-cells. Upsala Journal of Medical Sciences. 2016;**121**(2):113-119

[11] Desimone ME, Weinstock RS. Non-diabetic hypoglycemia. Available from: https://www.ncbi.nlm.nih. gov/books/NBK355894/ [Accessed: 25-June-2019]

[12] Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2009;**94**:709-728

[13] Shafiee G, Mohajeri-Tehrani M, Pajouhi M, Larijani B. The importance of hypoglycemia in diabetic patients. Journal of Diabetes & Metabolic Disorders. 2012;**11**(1):17

[14] Malouf R, Brust JC. Hypoglycemia: Causes, neurological manifestations, and outcome. Annals of Neurology. 1985;**17**:421-430

[15] Heller S, Damm P, Mersebach H, Vang Skjøth T, Kaaja R, Hod M, et al. Hypoglycemia in type 1 diabetic pregnancy: Role of preconception insulin aspart treatment in a randomized study. Diabetes Care. 2010;**33**:473-477

[16] Evers IM, ter Braak EW, de Valk HW, van DerSchoot B, Janssen N, Visser GH. Risk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy. Diabetes Care. 2002;**25**:554-559

[17] https://www.healthline.com/health/ pregnancy/hypoglycemic-and-pregnant [Accessed: 25-June-2019]

[18] The diabetes control and complications trial research group. Adverse events and their association with treatment regimens in the diabetes control and complications trial. Diabetes Care. 1995;**18**:1415-1427

**77**

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

[19] http://www.diabetes.org/livingwith-diabetes/treatment-and-care/ blood-glucose-control/hypoglycemia-

[20] Nielsen L, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen E. Hypoglycemia in pregnant women with type 1 diabetes. Predictors and role of metabolic control. Diabetes

low-blood.html [Accessed:

Care. 2008;**31**(1):9-14

2016;**8**:519-527

[21] Farrar D. Hyperglycemia in pregnancy: Prevalence, impact, and management challenges. International

Journal of Women's Health.

25-June-2019]

*Carbohydrate Metabolism in Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.88362*

[19] http://www.diabetes.org/livingwith-diabetes/treatment-and-care/ blood-glucose-control/hypoglycemialow-blood.html [Accessed: 25-June-2019]

[20] Nielsen L, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen E. Hypoglycemia in pregnant women with type 1 diabetes. Predictors and role of metabolic control. Diabetes Care. 2008;**31**(1):9-14

[21] Farrar D. Hyperglycemia in pregnancy: Prevalence, impact, and management challenges. International Journal of Women's Health. 2016;**8**:519-527

**76**

*Blood Glucose Levels*

**References**

2012;**32**:1222-1232

2014;**5**:760-761

[1] Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. Journal of Cerebral Blood Flow and Metabolism.

[11] Desimone ME, Weinstock RS. Non-diabetic hypoglycemia. Available from: https://www.ncbi.nlm.nih. gov/books/NBK355894/ [Accessed:

[12] Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism.

[13] Shafiee G, Mohajeri-Tehrani M, Pajouhi M, Larijani B. The importance of hypoglycemia in diabetic patients. Journal of Diabetes & Metabolic

[14] Malouf R, Brust JC. Hypoglycemia: Causes, neurological manifestations, and outcome. Annals of Neurology.

[15] Heller S, Damm P, Mersebach H, Vang Skjøth T, Kaaja R, Hod M, et al. Hypoglycemia in type 1 diabetic pregnancy: Role of preconception insulin aspart treatment in a randomized study. Diabetes Care. 2010;**33**:473-477

[16] Evers IM, ter Braak EW, de Valk HW, van DerSchoot B, Janssen N, Visser GH. Risk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy. Diabetes

[17] https://www.healthline.com/health/ pregnancy/hypoglycemic-and-pregnant

25-June-2019]

2009;**94**:709-728

1985;**17**:421-430

Care. 2002;**25**:554-559

[Accessed: 25-June-2019]

[18] The diabetes control and complications trial research group. Adverse events and their association with treatment regimens in the diabetes

control and complications trial. Diabetes Care. 1995;**18**:1415-1427

Disorders. 2012;**11**(1):17

[2] Rich L, Brown AM. Glycogen: Multiple roles in the CNS. The Neuroscientist. 2017;**23**(4):356-363

[3] Mergenthaler P, Lindauer U,

Dienel G, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends in Neurosciences. 2013;**36**(10):587-597

[4] Slavin J, Carlson J. American society for nutrition. Advances in Nutrition.

[5] Güemes M, Rahman S, Hussain K. What is a normal blood glucose? Archives of Disease in Childhood. 2015;**0**:1-6

[6] Röder P, Wu B, Liu Y, Han W. Pancreatic regulation of glucose

[7] Hill N, Oliver N, Choudhary P, Levy J, Hindmarsh P, Matthews D. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technology & Therapeutics.

Medicine. 2016;**48**:e219

2011;**13**(9):921-928

2013;**46**:1339-1352

[8] Dashty M. A quick look at biochemistry: Carbohydrate metabolism. Clinical Biochemistry.

[9] Slavin J, Carlson J. Carbohydrates. Advances in Nutrition. 2014;**5**:760-761

[10] Briant L, Salehi A, Vergari E, Zhang Q, Rorsman P. Glucagon secretion from pancreatic a-cells. Upsala Journal of Medical Sciences. 2016;**121**(2):113-119

homeostasis. Experimental & Molecular

**79**

**Chapter 6**

**Abstract**

**1. Introduction**

Symptoms of Hypoglycaemia

*Panagiota Loumpardia and Mohammed S.B. Huda*

interventions to modify or restore hypoglycaemia symptoms.

prevalence of severe hypoglycaemia can be up to 30–40% [2].

and the underlying pathophysiology.

**2. Definition of hypoglycaemia**

purpose of the study.

Hypoglycaemia is common in clinical practice for people with diabetes. However, the symptoms can vary between individuals and at different stages of their condition. Moreover, several factors influence symptoms experienced by people with diabetes, and many are amenable to intervention. Symptoms are commonly neuroglycopenic or neurogenic in aetiology, and these lead to different clusters of symptoms. Certain patient groups such as the elderly and pregnant women are particularly susceptible to hypoglycaemia. In this chapter, we describe the physiology and pathophysiology behind the symptoms of hypoglycaemia, with reference to current knowledge from neuroimaging studies, and outline potential

**Keywords:** hypoglycaemia, symptoms, treatment, hypoglycaemic unawareness

Hypoglycaemia is common in clinical practice with up to 45% of people with type 1 diabetes mellitus (T1DM) experiencing mild to moderate hypoglycaemia and 6% experiencing severe hypoglycaemia [1]. The average individual with type 1 diabetes experiences two symptomatic hypoglycaemic episodes a week, and the

The signs and symptoms of hypoglycaemia however can be variable and can change over time. In this chapter, we discuss the presentations of hypoglycaemia

This has been a controversial area for many years, and only recently, a consensus

The International Study Group suggests that a level of <3.0 mmol/l (54 mg/dl) be defined as denoting serious clinically important hypoglycaemia, whether that level is associated with symptoms or not, and that incidences of hypoglycaemia within that range be reported during clinical trials and in clinical practice [3].

The statement outlines proposed glucose levels to define severe hypoglycaemia as:

• Level 1: a glucose alert value of 3.9 mmol/l (70 mg/dl) or less. This need not be reported routinely in clinical studies, although this would depend upon the

has been developed. Normal blood glucose levels can range between 3.5 mmol/l (63 mg/dl) and 7.0 mmol/l (126 mg/dl), but individuals can develop lower values physiologically during fasting or starvation. Blood glucose levels less than

3.0 mmol/l (54 mg/dl) are associated with poorer clinical outcomes.

#### **Chapter 6**

## Symptoms of Hypoglycaemia

*Panagiota Loumpardia and Mohammed S.B. Huda*

#### **Abstract**

Hypoglycaemia is common in clinical practice for people with diabetes. However, the symptoms can vary between individuals and at different stages of their condition. Moreover, several factors influence symptoms experienced by people with diabetes, and many are amenable to intervention. Symptoms are commonly neuroglycopenic or neurogenic in aetiology, and these lead to different clusters of symptoms. Certain patient groups such as the elderly and pregnant women are particularly susceptible to hypoglycaemia. In this chapter, we describe the physiology and pathophysiology behind the symptoms of hypoglycaemia, with reference to current knowledge from neuroimaging studies, and outline potential interventions to modify or restore hypoglycaemia symptoms.

**Keywords:** hypoglycaemia, symptoms, treatment, hypoglycaemic unawareness

#### **1. Introduction**

Hypoglycaemia is common in clinical practice with up to 45% of people with type 1 diabetes mellitus (T1DM) experiencing mild to moderate hypoglycaemia and 6% experiencing severe hypoglycaemia [1]. The average individual with type 1 diabetes experiences two symptomatic hypoglycaemic episodes a week, and the prevalence of severe hypoglycaemia can be up to 30–40% [2].

The signs and symptoms of hypoglycaemia however can be variable and can change over time. In this chapter, we discuss the presentations of hypoglycaemia and the underlying pathophysiology.

#### **2. Definition of hypoglycaemia**

This has been a controversial area for many years, and only recently, a consensus has been developed. Normal blood glucose levels can range between 3.5 mmol/l (63 mg/dl) and 7.0 mmol/l (126 mg/dl), but individuals can develop lower values physiologically during fasting or starvation. Blood glucose levels less than 3.0 mmol/l (54 mg/dl) are associated with poorer clinical outcomes.

The International Study Group suggests that a level of <3.0 mmol/l (54 mg/dl) be defined as denoting serious clinically important hypoglycaemia, whether that level is associated with symptoms or not, and that incidences of hypoglycaemia within that range be reported during clinical trials and in clinical practice [3].

The statement outlines proposed glucose levels to define severe hypoglycaemia as:

• Level 1: a glucose alert value of 3.9 mmol/l (70 mg/dl) or less. This need not be reported routinely in clinical studies, although this would depend upon the purpose of the study.


#### **2.1 Symptoms**

The most frequently reported symptoms during hypoglycaemia in diabetes are sweating, trembling, inability to concentrate, weakness, hunger and blurred vision [4].

Generally, symptoms are divided into two groups:

a.Neuroglycopenic symptoms caused by brain glucose deprivation:


b.Neurogenic symptoms caused by the sympathoadrenal response:


To try and understand why the above symptoms are present, or not present, we describe physiological and pathophysiological response to hypoglycaemia in people with diabetes.

Glucose is the fuel for the most of the body functions including cerebral function. The brain is not able to synthesize glucose and therefore is critically dependent on a continuous glucose supply from the circulation (20% of circulated glucose).

Glucose is transported into the brain across the blood–brain barrier by the glucose transporter protein GLUT-1, and antecedent hypoglycaemia causes upregulation of this transporter [6]. If however the glucose level falls quickly to critically low levels, then despite the upregulation of the transporter, the supply is not adequate, and it may lead to impairment of brain function.

#### **2.2 Physiological response to hypoglycaemia**

Normal body physiology (without diabetes) has a sequence of responses to handle hypoglycaemia.

The first response is to decrease insulin production from the β-cells and increase the glucose counter-regulatory (plasma glucose raising) hormones: glucagon and adrenaline. Glucagon and adrenaline are the principle hormones

**81**

unawareness.

*Symptoms of Hypoglycaemia*

*DOI: http://dx.doi.org/10.5772/intechopen.88674*

of carbohydrates (hunger) [7, 8].

**2.4 Hypoglycaemic unawareness**

medications often being started later.

**2.3 Pathophysiological response to hypoglycaemia**

defense mechanisms may be compromised due to:

insulin secretion may be impaired due to β-cell failure.

with complex tasks being affected earlier than simple tasks [11].

The attenuated sympathoadrenal response is responsible for the reduced neurogenic symptom responses, well known contributing to the syndrome of hypoglycaemic unawareness [7, 8]. The patient has less time or no time between the onset of symptoms and the development of severe neuroglycopenia (impaired awareness/unawareness). Hypoglycaemic unawareness prevents patients from taking corrective action by eating which can potentially lead to seizure/coma and permanent neurological damage, if prolonged and severe. Thus, for many T1DM patients, the immediate fear of hypoglycaemia exceeds the fear of long-term diabetes complications [12, 13]. **Figure 1** is a diagrammatic summary of the physiological response to hypoglycaemia as well as the alterations in diabetes and hypoglycaemic

In addition, certain drugs and alcohol may impair a patient's perception of these symptoms. Beta-blockers may diminish the effect of adrenaline, potentially leading to reduced adrenergic warning symptoms (i.e. tremor, palpitations). Beta-blockers are not contraindicated in diabetes, but they should be considered when dealing with recurrent hypoglycaemia or hypoglycaemic unawareness. Other factors that can modify physical symptoms of hypoglycaemia are listed in **Table 1**. Nocturnal hypoglycaemia that can affect a significant percentage of patients and can be

unrecognized is a contributing factor to hypoglycaemic unawareness.

The syndrome of defective glucose counter-regulation and hypoglycaemic unawareness usually develops early in T1DM and later in T2DM, due to differing rates of progressive beta-cell failure and also due to insulin or sulphonylurea

to protect against acute hypoglycaemia by stimulating gluconeogenesis. Other hormones, cortisol and growth hormone play a less important role during hypoglycaemia. However deficiencies of these hormones can lead directly or exacerbate hypoglycaemia (i.e. Addison's disease, hypopituitarism). As plasma glucose concentration progressively falls, the increasing sympathoadrenal (sympathetic and adrenomedullary) response leads to neurogenic symptoms. These symptoms cause awareness of hypoglycaemia that prompts behavioural defense of ingestion

However, in people with type 1 or type 2 diabetes mellitus (T2DM), the above

Relative or absolute therapeutic hyperinsulinemia may lead to hypoglycaemia without intervention. The physiological defense mechanism of downregulation of

β-cell failure is also associated with the loss of an appropriate increase in circulating glucagon [7–9]. In addition, the increase in circulating adrenalin is attenuated [7, 10]. Absent insulin/glucagon responses and attenuated epinephrine responses contribute to the clinical syndrome of defective glucose counter-regulation [7, 8, 10]. As a consequence of losing the physiological control of glucose homeostasis, the body will develop neuroglycopenic and neurogenic symptoms as already listed above. The glucose level at which cognitive function declines is subject to substantial variation (from levels between 3 and 4 mmol/l (54–72 mg/dl), whereas others continue to seemingly function with levels below 2.5 mmol/l (45 mg/dl). Almost all domains of cognitive function are potentially at risk during acute hypoglycaemia,

#### *Symptoms of Hypoglycaemia DOI: http://dx.doi.org/10.5772/intechopen.88674*

*Blood Glucose Levels*

**2.1 Symptoms**

vision [4].

• Seizure/coma.

with diabetes.

handle hypoglycaemia.

glucose).

• Level 2: a glucose level of <3.0 mmol/l (<54 mg/dl) is sufficiently low to

• Level 3: severe hypoglycaemia, as defined by the American Diabetes Association, denotes severe cognitive impairment requiring external assistance for recovery.

The most frequently reported symptoms during hypoglycaemia in diabetes are sweating, trembling, inability to concentrate, weakness, hunger and blurred

• Cognitive impairment (altered perception, poor concentration, slow/hesi-

• Psychomotor abnormalities (incoordination, unsteadiness, weakness).

• Permanent neurological damage if prolonged severe hypoglycaemia.

• Adrenergic (palpitations, tremulousness, anxiety, arousal, skin pallor/flush-

To try and understand why the above symptoms are present, or not present, we describe physiological and pathophysiological response to hypoglycaemia in people

Glucose is the fuel for the most of the body functions including cerebral function. The brain is not able to synthesize glucose and therefore is critically dependent on a continuous glucose supply from the circulation (20% of circulated

Glucose is transported into the brain across the blood–brain barrier by the glucose transporter protein GLUT-1, and antecedent hypoglycaemia causes upregulation of this transporter [6]. If however the glucose level falls quickly to critically low levels, then despite the upregulation of the transporter, the supply is not adequate,

Normal body physiology (without diabetes) has a sequence of responses to

The first response is to decrease insulin production from the β-cells and increase the glucose counter-regulatory (plasma glucose raising) hormones: glucagon and adrenaline. Glucagon and adrenaline are the principle hormones

a.Neuroglycopenic symptoms caused by brain glucose deprivation:

• Behavioural changes (irritation, frustration, refusal to help).

b.Neurogenic symptoms caused by the sympathoadrenal response:

ing or blotchy rashes, tingling around the mouth/lips).

• Cholinergic (sweating, hunger, paresthesia) [5].

and it may lead to impairment of brain function.

**2.2 Physiological response to hypoglycaemia**

indicate serious, clinically important hypoglycaemia.

Generally, symptoms are divided into two groups:

tant speech, slow decision-making).

**80**

to protect against acute hypoglycaemia by stimulating gluconeogenesis. Other hormones, cortisol and growth hormone play a less important role during hypoglycaemia. However deficiencies of these hormones can lead directly or exacerbate hypoglycaemia (i.e. Addison's disease, hypopituitarism). As plasma glucose concentration progressively falls, the increasing sympathoadrenal (sympathetic and adrenomedullary) response leads to neurogenic symptoms. These symptoms cause awareness of hypoglycaemia that prompts behavioural defense of ingestion of carbohydrates (hunger) [7, 8].

#### **2.3 Pathophysiological response to hypoglycaemia**

However, in people with type 1 or type 2 diabetes mellitus (T2DM), the above defense mechanisms may be compromised due to:

Relative or absolute therapeutic hyperinsulinemia may lead to hypoglycaemia without intervention. The physiological defense mechanism of downregulation of insulin secretion may be impaired due to β-cell failure.

β-cell failure is also associated with the loss of an appropriate increase in circulating glucagon [7–9]. In addition, the increase in circulating adrenalin is attenuated [7, 10]. Absent insulin/glucagon responses and attenuated epinephrine responses contribute to the clinical syndrome of defective glucose counter-regulation [7, 8, 10]. As a consequence of losing the physiological control of glucose homeostasis, the body will develop neuroglycopenic and neurogenic symptoms as already listed above. The glucose level at which cognitive function declines is subject to substantial variation (from levels between 3 and 4 mmol/l (54–72 mg/dl), whereas others continue to seemingly function with levels below 2.5 mmol/l (45 mg/dl). Almost all domains of cognitive function are potentially at risk during acute hypoglycaemia, with complex tasks being affected earlier than simple tasks [11].

#### **2.4 Hypoglycaemic unawareness**

The attenuated sympathoadrenal response is responsible for the reduced neurogenic symptom responses, well known contributing to the syndrome of hypoglycaemic unawareness [7, 8]. The patient has less time or no time between the onset of symptoms and the development of severe neuroglycopenia (impaired awareness/unawareness). Hypoglycaemic unawareness prevents patients from taking corrective action by eating which can potentially lead to seizure/coma and permanent neurological damage, if prolonged and severe. Thus, for many T1DM patients, the immediate fear of hypoglycaemia exceeds the fear of long-term diabetes complications [12, 13]. **Figure 1** is a diagrammatic summary of the physiological response to hypoglycaemia as well as the alterations in diabetes and hypoglycaemic unawareness.

In addition, certain drugs and alcohol may impair a patient's perception of these symptoms. Beta-blockers may diminish the effect of adrenaline, potentially leading to reduced adrenergic warning symptoms (i.e. tremor, palpitations). Beta-blockers are not contraindicated in diabetes, but they should be considered when dealing with recurrent hypoglycaemia or hypoglycaemic unawareness. Other factors that can modify physical symptoms of hypoglycaemia are listed in **Table 1**. Nocturnal hypoglycaemia that can affect a significant percentage of patients and can be unrecognized is a contributing factor to hypoglycaemic unawareness.

The syndrome of defective glucose counter-regulation and hypoglycaemic unawareness usually develops early in T1DM and later in T2DM, due to differing rates of progressive beta-cell failure and also due to insulin or sulphonylurea medications often being started later.

#### **Figure 1.**

*A schematic diagram describing the physiological response to hypoglycaemia.*

1.Posture (the intensity of autonomic symptoms is greater in erect position compared to supine position) 2.Medications—toxins


#### **Table 1.**

*Factors that alter hypoglycaemic symptoms.*

#### **2.5 Hypoglycaemia-associated autonomic failure (HAAF)**

HAAF is a dynamic functional disorder that includes several episodes of recent antecedent hypoglycaemia, combined with previous exercise or sleep, and causes defective glucose counter-regulation and hypoglycaemic unawareness. Late post-exercise hypoglycaemia occurs 6–15 h after strenuous exercise and is often nocturnal [14, 15]. Sleep-related HAAF is the result of further attenuation of the sympathoadrenal response to hypoglycaemia during sleep [16–18]. Subsequently, a vicious cycle of recurrent iatrogenic hypoglycaemia may occur. HAAF is distinct from the autonomic neuropathy. However, HAAF is more prominent in people with diabetic autonomic neuropathy [19, 20].

#### **2.6 Symptoms in different groups**

#### *2.6.1 Children*

Symptoms in children differ from those in adults. Children have a more vigorous catecholamine response to hypoglycaemia than adults. Behavioural changes such as irritability, stubbornness, quietness and tantrums may be the primary features of low blood glucose in children [21].

#### *2.6.2 Elderly*

This age group may have a more limited perception of autonomic symptoms of hypoglycaemia, which they report as lower intensity than young people. Therefore, older people are at greater risk of developing neuroglycopenia, as the warning symptoms do not always precede the development of cognitive dysfunction [22]. This may reduce the opportunity to take appropriate treatment before developing disabling confusion and neuroglycopenia. It is worth mentioning that the frequency of hypoglycaemia in this group is probably underestimated. This is partly because of inadequate

**83**

*Symptoms of Hypoglycaemia*

*2.6.3 Pregnancy*

glucose levels.

mia than healthy controls [26].

hypoglycaemia.

**2.8 Reversing hypoglycaemic unawareness**

*DOI: http://dx.doi.org/10.5772/intechopen.88674*

education in elderly or their relatives, and also frequently hypoglycaemic events are misinterpreted as TIAs, vertebrobasilar insufficiency and vasovagal attacks [23].

It has been suggested that the intensity of the warning symptoms may be blunted during pregnancy [24, 25]. Of course this is very difficult to be study due to the ethical constraints surrounding the deliberate induction of experimental hypoglycaemia in early pregnancy. Considering that during pregnancy, women aim for stricter glycemic control, it is very difficult to distinguish whether the symptomatology is a true alteration in the symptomatic response or the result of tight

Recurrent hypoglycaemia which impairs awareness and the subsequent brain adaption is of scientific interest but incompletely understood. Several studies have been performed in order to understand brain network function during declining

Studies have shown significant EEG changes in euglycemia and hypoglycaemia during day and night in children with T1DM (20). Various neuroimaging techniques have been employed to study brain glucose metabolism including positron emission tomography (PET), magnetic resonance spectroscopy (MRS), functional magnetic

Studies that have employed the above techniques have shown that cerebral glucose metabolism appears to be largely maintained during moderate hypoglycaemia. However, recurrent hypoglycaemia may initiate cerebral adaptions at many different levels. There is interference with the accurate detection of hypoglycaemia, probably occurring at the level of the ventromedial hypothalamus. Brain areas that control appetite and induce fear and anxiety may not become activated during hypoglycaemia. The underlying mechanisms, as to whether altered glucose uptake or neuronal activation or both in the hypothalamic area is responsible, remain unclear. Interestingly, patients with T1DM (particularly with impaired awareness) seem to be better able in maintaining brain glucose metabolism during hypoglycae-

Avoidance of hypoglycaemic events enables people with unawareness to regain their symptoms when the glucose level is low. Often, preventing hypoglycaemia for 2 weeks results in increased symptoms of a low blood glucose and a return to nearly normal symptoms after 3 months. There are different strategies that can be used in clinical practice to enable avoidance of hypoglycaemia. Some are listed below:

• *Education*: educating patients in insulin adjustment is important. For example, a UK-based structured education program, Dose Adjustment for Normal eating (DAFNE), restores awareness in 43% of people with impaired awareness of hypoglycaemia [27]. Similarly, the HypoCOMPaSS trial showed that education around the prompt treatment of hypoglycaemia was as important as technolo-

• *Set blood sugar targets higher*: this can lead to decreased frequency of

gies such as insulin pump therapy and glucose sensors [28].

glycemic control and increased antecedent hypoglycaemia.

**2.7 Functional and metabolic studies during hypoglycaemia**

resonance imaging (fMRI) and arterial spin labelling (ASL) [26].

education in elderly or their relatives, and also frequently hypoglycaemic events are misinterpreted as TIAs, vertebrobasilar insufficiency and vasovagal attacks [23].

#### *2.6.3 Pregnancy*

*Blood Glucose Levels*

**Figure 1.**

**Table 1.**

2.Medications—toxins

beta-blockers)

*Factors that alter hypoglycaemic symptoms.*

**2.5 Hypoglycaemia-associated autonomic failure (HAAF)**

*A schematic diagram describing the physiological response to hypoglycaemia.*

• Magnitude of symptomatic response (i.e. caffeine)

diabetic autonomic neuropathy [19, 20].

**2.6 Symptoms in different groups**

low blood glucose in children [21].

*2.6.1 Children*

*2.6.2 Elderly*

HAAF is a dynamic functional disorder that includes several episodes of recent antecedent hypoglycaemia, combined with previous exercise or sleep, and causes defective glucose counter-regulation and hypoglycaemic unawareness. Late post-exercise hypoglycaemia occurs 6–15 h after strenuous exercise and is often nocturnal [14, 15]. Sleep-related HAAF is the result of further attenuation of the sympathoadrenal response to hypoglycaemia during sleep [16–18]. Subsequently, a vicious cycle of recurrent iatrogenic hypoglycaemia may occur. HAAF is distinct from the autonomic neuropathy. However, HAAF is more prominent in people with

1.Posture (the intensity of autonomic symptoms is greater in erect position compared to supine position)

• Impairing ability to perceive and interpret symptoms (i.e. hypnotic medications, alcohol,

Symptoms in children differ from those in adults. Children have a more vigorous catecholamine response to hypoglycaemia than adults. Behavioural changes such as irritability, stubbornness, quietness and tantrums may be the primary features of

This age group may have a more limited perception of autonomic symptoms of hypoglycaemia, which they report as lower intensity than young people. Therefore, older people are at greater risk of developing neuroglycopenia, as the warning symptoms do not always precede the development of cognitive dysfunction [22]. This may reduce the opportunity to take appropriate treatment before developing disabling confusion and neuroglycopenia. It is worth mentioning that the frequency of hypoglycaemia in this group is probably underestimated. This is partly because of inadequate

**82**

It has been suggested that the intensity of the warning symptoms may be blunted during pregnancy [24, 25]. Of course this is very difficult to be study due to the ethical constraints surrounding the deliberate induction of experimental hypoglycaemia in early pregnancy. Considering that during pregnancy, women aim for stricter glycemic control, it is very difficult to distinguish whether the symptomatology is a true alteration in the symptomatic response or the result of tight glycemic control and increased antecedent hypoglycaemia.

#### **2.7 Functional and metabolic studies during hypoglycaemia**

Recurrent hypoglycaemia which impairs awareness and the subsequent brain adaption is of scientific interest but incompletely understood. Several studies have been performed in order to understand brain network function during declining glucose levels.

Studies have shown significant EEG changes in euglycemia and hypoglycaemia during day and night in children with T1DM (20). Various neuroimaging techniques have been employed to study brain glucose metabolism including positron emission tomography (PET), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI) and arterial spin labelling (ASL) [26].

Studies that have employed the above techniques have shown that cerebral glucose metabolism appears to be largely maintained during moderate hypoglycaemia. However, recurrent hypoglycaemia may initiate cerebral adaptions at many different levels. There is interference with the accurate detection of hypoglycaemia, probably occurring at the level of the ventromedial hypothalamus. Brain areas that control appetite and induce fear and anxiety may not become activated during hypoglycaemia. The underlying mechanisms, as to whether altered glucose uptake or neuronal activation or both in the hypothalamic area is responsible, remain unclear. Interestingly, patients with T1DM (particularly with impaired awareness) seem to be better able in maintaining brain glucose metabolism during hypoglycaemia than healthy controls [26].

#### **2.8 Reversing hypoglycaemic unawareness**

Avoidance of hypoglycaemic events enables people with unawareness to regain their symptoms when the glucose level is low. Often, preventing hypoglycaemia for 2 weeks results in increased symptoms of a low blood glucose and a return to nearly normal symptoms after 3 months. There are different strategies that can be used in clinical practice to enable avoidance of hypoglycaemia. Some are listed below:


### **3. Conclusions**

Hypoglycaemia symptoms are variable and usually arise from impairment in counter-regulatory hormone or sympathoadrenal responses. Certain patient groups such as children, the elderly and pregnant women may be particularly vulnerable. A degree of hypoglycaemic unawareness is often a consequence of recurrent hypoglycaemia and can be challenging to manage. Various strategies including education, technology and islet/pancreas transplants may all be useful.

### **Conflicts of interest**

None declared.

### **Author details**

Panagiota Loumpardia and Mohammed S.B. Huda\* Department of Diabetes and Metabolism, St Bartholomew's and Royal London Hospitals, Barts Health NHS Trust, London, UK

\*Address all correspondence to: bobby.huda1@nhs.net

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**85**

*Symptoms of Hypoglycaemia*

**References**

[1] Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC,

2015;**10**(6):e0126427

Monitor. 2009;**21**:210-218

[4] Hepburn DA, Deary IJ,

on counterregulation and

1998;**21**(11):1960-1966

[7] Cryer PE. The barrier of

Pathophysiology, Prevalence,

2008;**57**(12):3169-3176

2012;**4**(5):e00093

Gray LJ, Davies MJ, et al. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A

systematic review and meta-analysis of population based studies. PLoS One.

[2] Frier BM. The incidence and impact of hypoglycemia in type 1 and type 2 diabetes. International Diabetes

[3] International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 Mmol/L (54 Mg/DL) should be reported in clinical trials: A joint position statement of the American Diabetes Association and the European Association for the Study of diabetes. Diabetes Care. 2017;**40**(1):155-157

Frier BM. Classification of symptoms of hypoglycaemia in insulin-treated diabetic patients using factor analysis: Relationship to hypoglycaemia unawareness. Diabetic Medicine: A Journal of the British Diabetic Association. 1992;**9**(1):70-75

[5] Meyer C, Grossmann R, Mitrakou A, Mahler R, Veneman T, Gerich J, et al. Effects of autonomic neuropathy

awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care.

[6] Dienel GA. Fueling and imaging brain activation. ASN Neuro.

hypoglycemia in diabetes. Diabetes.

[8] Cryer P. Hypoglycemia in Diabetes:

*DOI: http://dx.doi.org/10.5772/intechopen.88674*

and Prevention. American Diabetes Association; 2016. ISBN:

[9] Cryer PE. Mechanisms of

failure in insulin-dependent

1993;**91**(3):819-828

2013;**36**(10):3240-3246

1994;**43**(11):1378-1389

2008;**57**(9):2259-2268

Care. 1987;**10**(5):584-588

2006;**29**(1):20-25

Mauras N, Buckingham BA, Weinzimer SA, et al. The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care.

[16] Banarer S, Cryer PE. Sleeprelated hypoglycemia-associated autonomic failure in type 1 diabetes:

[12] Cryer PE. Banting lecture. Hypoglycemia: The limiting factor in the management of IDDM. Diabetes.

[13] Sherwin RS. Bringing light to the dark side of insulin. Diabetes.

[14] MacDonald MJ. Postexercise late-onset hypoglycemia in insulindependent diabetic patients. Diabetes

[15] Tansey MJ, Tsalikian E, Beck RW,

hypoglycemia-associated autonomic failure in diabetes. New England Journal of Medicine. 2013;**369**(4):362-372

[10] Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic

diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. Journal of Clinical Investigation.

[11] Graveling AJ, Deary IJ, Frier BM. Acute hypoglycemia impairs executive cognitive function in adults with and without type 1 diabetes. Diabetes Care.

978-1-58040-649-9

*Symptoms of Hypoglycaemia DOI: http://dx.doi.org/10.5772/intechopen.88674*

#### **References**

*Blood Glucose Levels*

**3. Conclusions**

**Conflicts of interest**

None declared.

and restoring unawareness [29].

**84**

**Author details**

Panagiota Loumpardia and Mohammed S.B. Huda\*

\*Address all correspondence to: bobby.huda1@nhs.net

Hospitals, Barts Health NHS Trust, London, UK

provided the original work is properly cited.

Department of Diabetes and Metabolism, St Bartholomew's and Royal London

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

• *Insulin pumps and continuous glucose sensors*: insulin pump therapy, particularly sensor-augmented insulin pumps, has a role in reducing severe hypoglycaemia

• *Islet cell transplantation/pancreatic transplant*: studies suggest immediate improvement of hypoglycaemic awareness in cases of functioning islet transplantation [30]. Reversal of hypoglycaemia-associated autonomic failure is responsible for the long-term maintenance of hypoglycaemic awareness that

Hypoglycaemia symptoms are variable and usually arise from impairment in counter-regulatory hormone or sympathoadrenal responses. Certain patient groups such as children, the elderly and pregnant women may be particularly vulnerable. A degree of hypoglycaemic unawareness is often a consequence of recurrent hypoglycaemia and can be challenging to manage. Various strategies including education,

returns after islet cell/pancreas transplantation [31].

technology and islet/pancreas transplants may all be useful.

[1] Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ, et al. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A systematic review and meta-analysis of population based studies. PLoS One. 2015;**10**(6):e0126427

[2] Frier BM. The incidence and impact of hypoglycemia in type 1 and type 2 diabetes. International Diabetes Monitor. 2009;**21**:210-218

[3] International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 Mmol/L (54 Mg/DL) should be reported in clinical trials: A joint position statement of the American Diabetes Association and the European Association for the Study of diabetes. Diabetes Care. 2017;**40**(1):155-157

[4] Hepburn DA, Deary IJ, Frier BM. Classification of symptoms of hypoglycaemia in insulin-treated diabetic patients using factor analysis: Relationship to hypoglycaemia unawareness. Diabetic Medicine: A Journal of the British Diabetic Association. 1992;**9**(1):70-75

[5] Meyer C, Grossmann R, Mitrakou A, Mahler R, Veneman T, Gerich J, et al. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care. 1998;**21**(11):1960-1966

[6] Dienel GA. Fueling and imaging brain activation. ASN Neuro. 2012;**4**(5):e00093

[7] Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;**57**(12):3169-3176

[8] Cryer P. Hypoglycemia in Diabetes: Pathophysiology, Prevalence,

and Prevention. American Diabetes Association; 2016. ISBN: 978-1-58040-649-9

[9] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. New England Journal of Medicine. 2013;**369**(4):362-372

[10] Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. Journal of Clinical Investigation. 1993;**91**(3):819-828

[11] Graveling AJ, Deary IJ, Frier BM. Acute hypoglycemia impairs executive cognitive function in adults with and without type 1 diabetes. Diabetes Care. 2013;**36**(10):3240-3246

[12] Cryer PE. Banting lecture. Hypoglycemia: The limiting factor in the management of IDDM. Diabetes. 1994;**43**(11):1378-1389

[13] Sherwin RS. Bringing light to the dark side of insulin. Diabetes. 2008;**57**(9):2259-2268

[14] MacDonald MJ. Postexercise late-onset hypoglycemia in insulindependent diabetic patients. Diabetes Care. 1987;**10**(5):584-588

[15] Tansey MJ, Tsalikian E, Beck RW, Mauras N, Buckingham BA, Weinzimer SA, et al. The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care. 2006;**29**(1):20-25

[16] Banarer S, Cryer PE. Sleeprelated hypoglycemia-associated autonomic failure in type 1 diabetes: Reduced awakening from sleep during hypoglycemia. Diabetes. 2003;**52**(5):1195-1203

[17] Jones TW, Porter P, Sherwin RS, Davis EA, O'Leary P, Frazer F, et al. Decreased epinephrine responses to hypoglycemia during sleep. The New England Journal of Medicine. 1998;**338**(23):1657-1662

[18] Schultes B, Jauch-Chara K, Gais S, Hallschmid M, Reiprich E, Kern W, et al. Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. PLoS Medicine. 2007;**4**(2):e69

[19] Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, et al. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: Evidence for a nonselective defect. Diabetes. 1997;**46**(5):814-823

[20] Hansen GL, Foli-Andersen P, Fredheim S, Juhl C, Remvig LF, Rose MH, et al. Hypoglycemia-associated EEG changes in prepubertal children with type 1 diabetes. Journal of Diabetes Science and Technology. 1 Nov 2016;**10**(6):1222-1229. [Accessed: April 22, 2019]

[21] McCrimmon RJ, Gold AE, Deary IJ, Kelnar CJ, Frier BM. Symptoms of hypoglycemia in children with IDDM. Diabetes Care. 1995;**18**(6):858-861

[22] Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA. Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care. 1997;**20**(2):135-141

[23] McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabetic Medicine: A Journal of the British Diabetic Association. 2001;**18**(9):690-705

[24] Rayburn W, Piehl E, Jacober S, Schork A, Ploughman L. Severe hypoglycemia during pregnancy: Its frequency and predisposing factors in diabetic women. International Journal of Gynaecology and Obstetrics: The Official Organ of the International Federation of Gynaecology and Obstetrics. 1986;**24**(4):263-268

[25] Kimmerle R, Heinemann L, Delecki A, Berger M. Severe hypoglycemia incidence and predisposing factors in 85 pregnancies of type I diabetic women. Diabetes Care. 1992;**15**(8):1034-1037

[26] Rooijackers HMM, Wiegers EC, Tack CJ, van der Graaf M, de Galan BE. Brain glucose metabolism during hypoglycemia in type 1 diabetes: Insights from functional and metabolic neuroimaging studies. Cellular and Molecular Life Sciences: CMLS. 2016;**73**(4):705-722

[27] Nicole de Z, Rogers H, Stadler M, Gianfrancesco C, Beveridge S, Britneff E, et al. A psychoeducational program to restore hypoglycemia awareness: The DAFNE-HART pilot study. Diabetes Care. 2014;**37**(3):863-866

[28] Little SA, Speight J, Leelarathna L, Walkinshaw E, Tan HK, Bowes A, et al. Sustained reduction in severe hypoglycemia in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia: Twoyear follow-up in the HypoCOMPaSS randomized clinical trial. Diabetes Care. 2018;**41**(8):1600-1607

[29] Bosi E, Choudhary P, de Valk HW, Lablanche S, Castañeda J, de Portu S, et al. Efficacy and safety of suspendbefore-low insulin pump technology in hypoglycaemia-prone adults with type 1 diabetes (SMILE): An openlabel randomised controlled trial. The Lancet. Diabetes and Endocrinology. 2019;**7**(6):462-472

**87**

*Symptoms of Hypoglycaemia*

Research. 2015;**98**:86-91

2015;**31**(6):646-650

*DOI: http://dx.doi.org/10.5772/intechopen.88674*

[30] Maffi P, Secchi A. Clinical results of islet transplantation. Pharmacological

[31] Kamel JT, Goodman DJ, Howe K, Cook MJ, Ward GM, Roberts LJ. Assessment of the relationship

between hypoglycaemia awareness and autonomic function following islet cell/ pancreas transplantation. Diabetes/ Metabolism Research and Reviews.

*Symptoms of Hypoglycaemia DOI: http://dx.doi.org/10.5772/intechopen.88674*

*Blood Glucose Levels*

2003;**52**(5):1195-1203

1998;**338**(23):1657-1662

2007;**4**(2):e69

1997;**46**(5):814-823

22, 2019]

Reduced awakening from sleep during hypoglycemia. Diabetes.

[17] Jones TW, Porter P, Sherwin RS, Davis EA, O'Leary P, Frazer F, et al. Decreased epinephrine responses to hypoglycemia during sleep. The New England Journal of Medicine.

[24] Rayburn W, Piehl E, Jacober S, Schork A, Ploughman L. Severe hypoglycemia during pregnancy: Its frequency and predisposing factors in diabetic women. International Journal of Gynaecology and Obstetrics: The Official Organ of the International Federation of Gynaecology and Obstetrics. 1986;**24**(4):263-268

[25] Kimmerle R, Heinemann L, Delecki A, Berger M. Severe hypoglycemia incidence and

Care. 1992;**15**(8):1034-1037

2016;**73**(4):705-722

2018;**41**(8):1600-1607

2019;**7**(6):462-472

predisposing factors in 85 pregnancies of type I diabetic women. Diabetes

[26] Rooijackers HMM, Wiegers EC, Tack CJ, van der Graaf M, de Galan BE. Brain glucose metabolism during hypoglycemia in type 1 diabetes: Insights from functional and metabolic neuroimaging studies. Cellular and Molecular Life Sciences: CMLS.

[27] Nicole de Z, Rogers H, Stadler M, Gianfrancesco C, Beveridge S,

Britneff E, et al. A psychoeducational program to restore hypoglycemia awareness: The DAFNE-HART pilot study. Diabetes Care. 2014;**37**(3):863-866

[28] Little SA, Speight J, Leelarathna L, Walkinshaw E, Tan HK, Bowes A, et al. Sustained reduction in severe hypoglycemia in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia: Twoyear follow-up in the HypoCOMPaSS randomized clinical trial. Diabetes Care.

[29] Bosi E, Choudhary P, de Valk HW, Lablanche S, Castañeda J, de Portu S, et al. Efficacy and safety of suspendbefore-low insulin pump technology in hypoglycaemia-prone adults with type 1 diabetes (SMILE): An openlabel randomised controlled trial. The Lancet. Diabetes and Endocrinology.

[18] Schultes B, Jauch-Chara K, Gais S, Hallschmid M, Reiprich E, Kern W, et al. Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. PLoS Medicine.

[19] Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, et al. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: Evidence for a nonselective defect. Diabetes.

[20] Hansen GL, Foli-Andersen P, Fredheim S, Juhl C, Remvig LF,

[21] McCrimmon RJ, Gold AE, Deary IJ, Kelnar CJ, Frier BM. Symptoms of hypoglycemia in children with IDDM. Diabetes Care.

[22] Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA. Altered hierarchy of protective

responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care. 1997;**20**(2):135-141

[23] McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabetic Medicine: A Journal of the British Diabetic Association. 2001;**18**(9):690-705

1995;**18**(6):858-861

Rose MH, et al. Hypoglycemia-associated EEG changes in prepubertal children with type 1 diabetes. Journal of

Diabetes Science and Technology. 1 Nov 2016;**10**(6):1222-1229. [Accessed: April

**86**

[30] Maffi P, Secchi A. Clinical results of islet transplantation. Pharmacological Research. 2015;**98**:86-91

[31] Kamel JT, Goodman DJ, Howe K, Cook MJ, Ward GM, Roberts LJ. Assessment of the relationship between hypoglycaemia awareness and autonomic function following islet cell/ pancreas transplantation. Diabetes/ Metabolism Research and Reviews. 2015;**31**(6):646-650

**89**

**Chapter 7**

**Abstract**

hypoglycemia, insulin

**1. Introduction**

Guidelines

*Thenmozhi Paluchamy*

Hypoglycemia: Essential Clinical

Hypoglycemia is the acute complication of diabetes mellitus and the commonest diabetic emergency and is associated with considerable morbidity and mortality. It can be caused by too much insulin intake or oral hypoglycemic agents, too little food, or excessive physical activity. The level of glucose that produces symptoms of hypoglycemia varies from person to person and varies for the same person under different circumstances. It characterized by sweating, tremor, tachycardia, palpitation, nervousness, hunger, confusion, slurred speech, emotional changes, double vision, drowsiness, sleeplessness, and often self-diagnosed which may leads to serious symptoms of seizure, cognitive impairment, coma and death. The immediate treatment of hypoglycemia should be known by all the diabetic patients, so that need for hospitalization could be avoided. Hypoglycemia and its severity can be prevented by early recognition of hypoglycemia risk factors, self-monitoring of blood glucose, selection of appropriate treatment regimens, appropriate educational programs for healthcare professionals. The major challenges of the treatment of hypoglycemia are good glycemic control, minimize the risk of hypoglycemia and thereby minimize long-term complications. Hence there is an urgent need to understand the clinical spectrum and burden of hypoglycemia so that adequate control

measures can be implemented against this life-threatening complication.

The blood sugar level, blood sugar concentration, or blood glucose level is the amount of blood sugar level in the blood. Glucose is required for cellular respiration and is the preferred fuel for all body cells. Plasma glucose concentration is the balance between the rate of glucose entering the circulation and the rate of removal of glucose from the circulation. Circulating glucose comes from intestinal absorption from the ingestion of carbohydrate during the fed state and by the process of glycogenolysis, and gluconeogenesis in the fasting state. Glycogenolysis is the biochemical breakdown of glycogen into glucose which takes place in the cells of the muscle and liver in response to hormonal and neural signals. Gluconeogenesis is the metabolic process of generation of glucose from non-carbohydrate substances such as protein and fat which takes place in the liver and kidney in response to diabetogenic hormones. There are hormones involved in glucose regulation are called glucoregulatory hormones which include insulin, glucagon, amylin, glucogan-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), epinephrine,

**Keywords:** blood glucose, diabetes mellitus, glucagon, glycemic index,

**Chapter 7**

## Hypoglycemia: Essential Clinical Guidelines

*Thenmozhi Paluchamy*

#### **Abstract**

Hypoglycemia is the acute complication of diabetes mellitus and the commonest diabetic emergency and is associated with considerable morbidity and mortality. It can be caused by too much insulin intake or oral hypoglycemic agents, too little food, or excessive physical activity. The level of glucose that produces symptoms of hypoglycemia varies from person to person and varies for the same person under different circumstances. It characterized by sweating, tremor, tachycardia, palpitation, nervousness, hunger, confusion, slurred speech, emotional changes, double vision, drowsiness, sleeplessness, and often self-diagnosed which may leads to serious symptoms of seizure, cognitive impairment, coma and death. The immediate treatment of hypoglycemia should be known by all the diabetic patients, so that need for hospitalization could be avoided. Hypoglycemia and its severity can be prevented by early recognition of hypoglycemia risk factors, self-monitoring of blood glucose, selection of appropriate treatment regimens, appropriate educational programs for healthcare professionals. The major challenges of the treatment of hypoglycemia are good glycemic control, minimize the risk of hypoglycemia and thereby minimize long-term complications. Hence there is an urgent need to understand the clinical spectrum and burden of hypoglycemia so that adequate control measures can be implemented against this life-threatening complication.

**Keywords:** blood glucose, diabetes mellitus, glucagon, glycemic index, hypoglycemia, insulin

#### **1. Introduction**

The blood sugar level, blood sugar concentration, or blood glucose level is the amount of blood sugar level in the blood. Glucose is required for cellular respiration and is the preferred fuel for all body cells. Plasma glucose concentration is the balance between the rate of glucose entering the circulation and the rate of removal of glucose from the circulation. Circulating glucose comes from intestinal absorption from the ingestion of carbohydrate during the fed state and by the process of glycogenolysis, and gluconeogenesis in the fasting state. Glycogenolysis is the biochemical breakdown of glycogen into glucose which takes place in the cells of the muscle and liver in response to hormonal and neural signals. Gluconeogenesis is the metabolic process of generation of glucose from non-carbohydrate substances such as protein and fat which takes place in the liver and kidney in response to diabetogenic hormones. There are hormones involved in glucose regulation are called glucoregulatory hormones which include insulin, glucagon, amylin, glucogan-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), epinephrine,

cortisol, and growth hormone. Among, insulin and amylin are secreted from the β-cells of islets of Langerhans, glucagon from the α-cells of islets of Langerhans of the pancreas, GLP-1 from the small intestine and colon, and GIP from upper small intestine. If these glucoregulatory or counter-regulatory hormones fail to balance the blood sugar level causes hypoglycemia or hyperglycemia.

Hypoglycemia, also called low blood glucose or low blood sugar, occurs when the level of glucose in blood drops below normal. The term literally means "undersweet blood". It may also be referred to as an insulin reaction, or insulin shock. This condition typically arises from abnormalities in the mechanisms involved in glucose homeostasis. Hypoglycemia is the commonest diabetic emergency and is associated with considerable morbidity and mortality. The American Diabetes Association defines the hypoglycemia as any abnormally low plasma glucose concentration that exposes the subject to potential harm [1]. Hypoglycemia is common in insulin dependent diabetic patients and may also occur in patients with non-insulindependent diabetes mellitus. It can be caused by too much insulin intake or oral hypoglycemic agents or too little food or excessive physical activity [2]. The other causes or risk factors of hypoglycemia are dosage, combination of anti-diabetic drugs, timing of consuming the drug and anti-diabetic drug with simultaneous use of other interacting drugs. The symptoms of hypoglycemia depend on the level of blood glucose and vary from one person to another person and also vary within the same person under different circumstances [3]. It may range from a very mild with minimal or no symptoms (60–70 mg/dl), to severe hypoglycemia, and neurological impairment (<40 mg/dl) [4].

#### **2. Prevalence of hypoglycemia in diabetes**

Hypoglycemia is one of the most feared complications of diabetes treatment [5]. Individuals who take insulin, which includes all people with T1DM and some people with type 2 diabetes, are prone to hypoglycemia [6]. Hypoglycemia commonly occurs in clinical practice as approximately 90% of all patients who receive insulin have experienced hypoglycemic episodes [7]. Furthermore, surveys investigating the prevalence of hypoglycemia have provided some alarming results. The Diabetes Control and Complication Trial (DCCT) reported a threefold increase in severe hypoglycemia and coma in intensively treated T1DM patients versus conventionally treated patients [8]. A meta-analysis study reported that the prevalence of hypoglycemia was 45% for mild/moderate and 6% for severe. Incidence of hypoglycemic episodes per person-year for mild/moderate and for severe was 19 and 0.80, respectively. Hypoglycemia was prevalent among patients on insulin; among, the prevalence of mild-moderate and severe hypoglycemia episodes was 50 and 21%, respectively. Similarly, among patients on the treatment of sulfonylurea, the prevalence of mild-moderate and severe hypoglycemia was 30 and 5%. It was also found 5% of prevalence among those who did not include sulfonylureas in the treatment regime [9].

A population-based study conducted in the UK to determine the frequency and predictors of hypoglycemia in type one diabetic patients. The study findings concluded that type 1 diabetes mellitus patients who are on intensive treatment may experience up to 10 episodes of symptomatic hypoglycemia per week and severe temporarily disabling hypoglycemia at least once a year [10]. It is estimated that 2–4% of deaths occur in people with type 1 diabetes due to hypoglycemia [11]. Hypoglycemia is also equally common in type 2 diabetes, with prevalence rates of 70–80% [12]. Donnelly et al. who conducted a survey with 267 individuals with

**91**

**Table 1.**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

frequency to cause significant morbidity.

be the only sign of patients treated with β-blockers [14].

**Medical-related factors** • Strict glycemic control

• Previous history of severe hypoglycemia • Long duration of type 1 diabetes

• Lipohypertrophy at injection sites • Impaired awareness of hypoglycemia

ing renal replacement therapy)

• Cognitive dysfunction/dementia

• Severe hepatic dysfunction

• Sepsis

• Terminal illness

*Risk factors of hypoglycemia.*

• Duration of insulin therapy in type 2 diabetes

• Impaired renal function (including those patients requir-

• Inadequate treatment of previous hypoglycemia

**3. Risk factors for hypoglycemia**

type 1 diabetes and insulin-treated type 2 diabetes to record hypoglycemic events over a 4-week period and 155 individuals reported 572 incidents of hypoglycemia. Of these, the rate of hypoglycemia events in type 1 diabetic was 43 per patient per year whereas in type 2 diabetes was 16 events per patient per year. The predictor of hypoglycemia for individuals with type 1 diabetes and insulin-treated type 2 diabetes was a history of previous hypoglycemia and duration of insulin treatment [10]. Similarly other study findings also concluded that hypoglycemia occurs more often than previously reported [12] in insulin-treated type 2 diabetes and with sufficient

Several factors influence an individual at risk (**Table 1**) for a hypoglycemic episode. These include a mismatch in the timing, amount, or type of insulin, skipping meals, eating small meal, irregular dietary pattern and lack of physical activity. Additional factors such as alcohol consumption, obesity, elderly people, liver disorders, renal disease, adrenal insufficiency (glucocorticoid or catecholamine deficiencies) and pituitary insufficiency and leukemia which increase the risk for hypoglycemia. Other factors at risk are those who have ingested medication salicylates and those who have surgery with general anesthesia, which places them in an altered state of consciousness and hyper-metabolic state [13]. Another potential risk for hypoglycemia is the use of β-blocker and ACE inhibitor medication in cardiac and hypertensive patients which mask the symptoms of hypoglycemia. β-Blockers inhibit the secretion of insulin and glycogenolysis due to diminishing of adrenergic counter regulation and also conceal the symptoms of catecholamine-mediated neurogenic hypoglycemia such as tremor, palpitation, hunger, irritability and confusion. However sweating remains unmasked and may

**Lifestyle-related factors**

• Irregular lifestyle

monitoring

coeliac disease

resection **Other factors:**

• Alcohol • Increasing age • Early pregnancy • Breast feeding

• Increased exercise (relative to usual)

• No or inadequate blood glucose

• Bariatric surgery involving bowel

• Hypoglycemia unawareness

• Time since insulin initiated

**Reduced carbohydrate intake/absorption** • Food malabsorption, e.g., gastroenteritis,

• Number of years since diabetes diagnosis

#### *Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

*Blood Glucose Levels*

impairment (<40 mg/dl) [4].

**2. Prevalence of hypoglycemia in diabetes**

cortisol, and growth hormone. Among, insulin and amylin are secreted from the β-cells of islets of Langerhans, glucagon from the α-cells of islets of Langerhans of the pancreas, GLP-1 from the small intestine and colon, and GIP from upper small intestine. If these glucoregulatory or counter-regulatory hormones fail to balance

Hypoglycemia, also called low blood glucose or low blood sugar, occurs when the level of glucose in blood drops below normal. The term literally means "undersweet blood". It may also be referred to as an insulin reaction, or insulin shock. This condition typically arises from abnormalities in the mechanisms involved in glucose homeostasis. Hypoglycemia is the commonest diabetic emergency and is associated with considerable morbidity and mortality. The American Diabetes Association defines the hypoglycemia as any abnormally low plasma glucose concentration that exposes the subject to potential harm [1]. Hypoglycemia is common in insulin dependent diabetic patients and may also occur in patients with non-insulindependent diabetes mellitus. It can be caused by too much insulin intake or oral hypoglycemic agents or too little food or excessive physical activity [2]. The other causes or risk factors of hypoglycemia are dosage, combination of anti-diabetic drugs, timing of consuming the drug and anti-diabetic drug with simultaneous use of other interacting drugs. The symptoms of hypoglycemia depend on the level of blood glucose and vary from one person to another person and also vary within the same person under different circumstances [3]. It may range from a very mild with minimal or no symptoms (60–70 mg/dl), to severe hypoglycemia, and neurological

Hypoglycemia is one of the most feared complications of diabetes treatment [5]. Individuals who take insulin, which includes all people with T1DM and some people with type 2 diabetes, are prone to hypoglycemia [6]. Hypoglycemia commonly occurs in clinical practice as approximately 90% of all patients who receive insulin have experienced hypoglycemic episodes [7]. Furthermore, surveys investigating the prevalence of hypoglycemia have provided some alarming results. The Diabetes Control and Complication Trial (DCCT) reported a threefold increase in severe hypoglycemia and coma in intensively treated T1DM patients versus conventionally treated patients [8]. A meta-analysis study reported that the prevalence of hypoglycemia was 45% for mild/moderate and 6% for severe. Incidence of hypoglycemic episodes per person-year for mild/moderate and for severe was 19 and 0.80, respectively. Hypoglycemia was prevalent among patients on insulin; among, the prevalence of mild-moderate and severe hypoglycemia episodes was 50 and 21%, respectively. Similarly, among patients on the treatment of sulfonylurea, the prevalence of mild-moderate and severe hypoglycemia was 30 and 5%. It was also found 5% of prevalence among those who did not include sulfonylureas in the treatment

A population-based study conducted in the UK to determine the frequency and predictors of hypoglycemia in type one diabetic patients. The study findings concluded that type 1 diabetes mellitus patients who are on intensive treatment may experience up to 10 episodes of symptomatic hypoglycemia per week and severe temporarily disabling hypoglycemia at least once a year [10]. It is estimated that 2–4% of deaths occur in people with type 1 diabetes due to hypoglycemia [11]. Hypoglycemia is also equally common in type 2 diabetes, with prevalence rates of 70–80% [12]. Donnelly et al. who conducted a survey with 267 individuals with

the blood sugar level causes hypoglycemia or hyperglycemia.

**90**

regime [9].

type 1 diabetes and insulin-treated type 2 diabetes to record hypoglycemic events over a 4-week period and 155 individuals reported 572 incidents of hypoglycemia. Of these, the rate of hypoglycemia events in type 1 diabetic was 43 per patient per year whereas in type 2 diabetes was 16 events per patient per year. The predictor of hypoglycemia for individuals with type 1 diabetes and insulin-treated type 2 diabetes was a history of previous hypoglycemia and duration of insulin treatment [10]. Similarly other study findings also concluded that hypoglycemia occurs more often than previously reported [12] in insulin-treated type 2 diabetes and with sufficient frequency to cause significant morbidity.

#### **3. Risk factors for hypoglycemia**

Several factors influence an individual at risk (**Table 1**) for a hypoglycemic episode. These include a mismatch in the timing, amount, or type of insulin, skipping meals, eating small meal, irregular dietary pattern and lack of physical activity. Additional factors such as alcohol consumption, obesity, elderly people, liver disorders, renal disease, adrenal insufficiency (glucocorticoid or catecholamine deficiencies) and pituitary insufficiency and leukemia which increase the risk for hypoglycemia. Other factors at risk are those who have ingested medication salicylates and those who have surgery with general anesthesia, which places them in an altered state of consciousness and hyper-metabolic state [13].

Another potential risk for hypoglycemia is the use of β-blocker and ACE inhibitor medication in cardiac and hypertensive patients which mask the symptoms of hypoglycemia. β-Blockers inhibit the secretion of insulin and glycogenolysis due to diminishing of adrenergic counter regulation and also conceal the symptoms of catecholamine-mediated neurogenic hypoglycemia such as tremor, palpitation, hunger, irritability and confusion. However sweating remains unmasked and may be the only sign of patients treated with β-blockers [14].


**Table 1.** *Risk factors of hypoglycemia.*

#### **4. Causes of hypoglycemia**

Hypoglycemia is commonly occur in people with both type 1 and type 2 diabetes taking insulin or certain oral hypoglycemic agents. The common causes of hypoglycemia are:

#### **4.1 Insulin and oral hypoglycemic agents**

Diabetes medications such as insulin and Sulfonylureas are the most common causes of hypoglycemia in diabetic subjects [15]. Of these, Insulin is a definite cause of low blood glucose. One reason why newer insulin are preferred over NPH and regular insulin is that they are less likely to cause blood glucose lows, particularly overnight. Insulin pumps may also reduce the risk for low blood glucose. Accidentally injecting the wrong insulin type, too much insulin, or injecting directly into the muscle instead of subcutaneous can cause low blood glucose. The long-acting sulfonylureas such as glibenclamide and chlorpropamide are associated with more severe hypoglycemia than the shorter-acting drugs [16]. Metformin was the most frequent used oral hypoglycemic agents (66.4%) followed by sulfonylurea and the most prevalent combination therapy was metformin/glibenclamide regimen (28.5%). The majority of patients treated with metformin at the time when they were diagnosed with diabetes (45.3%). Hypoglycemic episodes were most commonly reported adverse events with insulin and gastric upset with oral hypoglycemic agents. 60.3% of the patients did not follow regular blood glucose checkup [17]. Several reports reveal that various pharmacological agents like metformin, rosiglitazone, etc., which have wide ranging side effects, including weight gain, hypoglycemia and risk of coronary heart disease [18]. Occasionally episodes of hypoglycemia may occur with metformin, as the most commonly used anti-diabetic drug, due to an imbalance between food intake and dose of metformin [19].

#### **4.2 Food pattern**

Eating foods with less carbohydrate than usual without reducing the amount of insulin taken. Timing of insulin based on whether consumption of carbohydrates is from liquids or solids which can affect blood glucose levels. Liquids are absorbed much faster than solids, so timing the insulin dose to the absorption of glucose from foods. The composition of the meal contains the amount of fat, protein, and fiber which can also affect the absorption of carbohydrates.

#### **4.3 Dietary habit**

If meal is skip or delay, blood glucose could drop too low. Hypoglycemia also can occur when asleep and have not eaten for several hours.

#### **4.4 Drinking alcohol**

Alcohol consumption increase the insulin secretion and makes the liver not to release the glucose effectively into the blood circulation especially if have not eaten enough food within around 6 h and also makes more difficulty to generate new glucose by liver. Hypoglycemia occur overnight if fall asleep after consuming alcohol without eating food among people with diabetes.

**93**

**Table 2.**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

**4.6 Potential causes of in-patient hypoglycemia**

• Misreading poorly written prescriptions

• Confusing the insulin name with the dose

• Incorrect prescription and administration insulin or oral

• Mismatch between insulin/oral hypoglycemic therapy

• Intravenous insulin infusion with or without glucose

• Failure to monitor blood glucose adequately especially on

• Acute withdrawal of long term steroid therapy • Recovery from stress of critical illness

• Inappropriate use of short acting insulin

hypoglycemic agent

• Polypharmacy

infusion

and meal or enteral feed

• Mobilization after illness • Amputation of limb

Intravenous insulin infusion

*Etiological factors of hypoglycemia.*

Exercise has plays a vital role and has many potential health benefits. However the exercise can lower blood glucose by utilizing glucose for energy. Nearly half of the individual with diabetes mellitus who exercised an hour during the day may experience a low blood glucose reaction overnight. The factors influencing exercise induce hypoglycemia are the intensity, timing of exercise and duration. Hypoglycemia can occur during, 1–2 h after, or up to 17 h after exercise. Endogenous insulin secretion is reduced up to 40–60% while doing moderateintensity exercise among non-diabetic individuals. Hence it is mandate that decrease insulin dose or increase glucose intake is recommended before, during or after exercise depending on the intensity of exercise to prevent exercise associated

Additionally, recent studies have observed the cruel cycle of counter-regulatory failure between exercise and hypoglycemia. Thus, subsequent two episodes of prolonged, moderate-intensity exercise can inhibit autonomic nervous system and neuroendocrine responses by 50%. Similarly, 40–50% of counter-regulatory responses reduced during two episodes of antecedent hypoglycemia due to subsequent exercise [20]. Hence, there is a greater risk of hypoglycemia during exercise among individuals who have had a previous episode of hypoglycemia. This may be prevented by adjusting pre-exercise insulin dose, and consuming appropriate amounts of glucose.

Common causes of inpatient hypoglycemia are listed in **Table 2**. One of the most

• Reduced carbohydrate intake than

• Poor coordination in meal and medica-

• Nausea and/or vomiting • Nothing by mouth orders • Delay in serving food tray

normal • Anorexia

tion timing • Skipping of meal

serious and common causes of inpatient hypoglycemia are insulin prescription

**Treatment-related causes Glucose intake-related causes**

**4.5 Physical activity**

hypoglycemia.

errors including:

#### **4.5 Physical activity**

*Blood Glucose Levels*

cemia are:

**4. Causes of hypoglycemia**

**4.1 Insulin and oral hypoglycemic agents**

intake and dose of metformin [19].

which can also affect the absorption of carbohydrates.

occur when asleep and have not eaten for several hours.

without eating food among people with diabetes.

**4.2 Food pattern**

**4.3 Dietary habit**

**4.4 Drinking alcohol**

Hypoglycemia is commonly occur in people with both type 1 and type 2 diabetes taking insulin or certain oral hypoglycemic agents. The common causes of hypogly-

Diabetes medications such as insulin and Sulfonylureas are the most common causes of hypoglycemia in diabetic subjects [15]. Of these, Insulin is a definite cause of low blood glucose. One reason why newer insulin are preferred over NPH and regular insulin is that they are less likely to cause blood glucose lows, particularly overnight. Insulin pumps may also reduce the risk for low blood glucose. Accidentally injecting the wrong insulin type, too much insulin, or injecting directly into the muscle instead of subcutaneous can cause low blood glucose. The long-acting sulfonylureas such as glibenclamide and chlorpropamide are associated with more severe hypoglycemia than the shorter-acting drugs [16]. Metformin was the most frequent used oral hypoglycemic agents (66.4%) followed by sulfonylurea and the most prevalent combination therapy was metformin/glibenclamide regimen (28.5%). The majority of patients treated with metformin at the time when they were diagnosed with diabetes (45.3%). Hypoglycemic episodes were most commonly reported adverse events with insulin and gastric upset with oral hypoglycemic agents. 60.3% of the patients did not follow regular blood glucose checkup [17]. Several reports reveal that various pharmacological agents like metformin, rosiglitazone, etc., which have wide ranging side effects, including weight gain, hypoglycemia and risk of coronary heart disease [18]. Occasionally episodes of hypoglycemia may occur with metformin, as the most commonly used anti-diabetic drug, due to an imbalance between food

Eating foods with less carbohydrate than usual without reducing the amount of insulin taken. Timing of insulin based on whether consumption of carbohydrates is from liquids or solids which can affect blood glucose levels. Liquids are absorbed much faster than solids, so timing the insulin dose to the absorption of glucose from foods. The composition of the meal contains the amount of fat, protein, and fiber

If meal is skip or delay, blood glucose could drop too low. Hypoglycemia also can

Alcohol consumption increase the insulin secretion and makes the liver not to release the glucose effectively into the blood circulation especially if have not eaten enough food within around 6 h and also makes more difficulty to generate new glucose by liver. Hypoglycemia occur overnight if fall asleep after consuming alcohol

**92**

Exercise has plays a vital role and has many potential health benefits. However the exercise can lower blood glucose by utilizing glucose for energy. Nearly half of the individual with diabetes mellitus who exercised an hour during the day may experience a low blood glucose reaction overnight. The factors influencing exercise induce hypoglycemia are the intensity, timing of exercise and duration. Hypoglycemia can occur during, 1–2 h after, or up to 17 h after exercise. Endogenous insulin secretion is reduced up to 40–60% while doing moderateintensity exercise among non-diabetic individuals. Hence it is mandate that decrease insulin dose or increase glucose intake is recommended before, during or after exercise depending on the intensity of exercise to prevent exercise associated hypoglycemia.

Additionally, recent studies have observed the cruel cycle of counter-regulatory failure between exercise and hypoglycemia. Thus, subsequent two episodes of prolonged, moderate-intensity exercise can inhibit autonomic nervous system and neuroendocrine responses by 50%. Similarly, 40–50% of counter-regulatory responses reduced during two episodes of antecedent hypoglycemia due to subsequent exercise [20]. Hence, there is a greater risk of hypoglycemia during exercise among individuals who have had a previous episode of hypoglycemia. This may be prevented by adjusting pre-exercise insulin dose, and consuming appropriate amounts of glucose.

#### **4.6 Potential causes of in-patient hypoglycemia**

Common causes of inpatient hypoglycemia are listed in **Table 2**. One of the most serious and common causes of inpatient hypoglycemia are insulin prescription errors including:


**Table 2.**

*Etiological factors of hypoglycemia.*


#### **5. Physiology of glucose counter-regulation**

The most metabolically active organ is brain and it is the first organ affected by lower blood glucose level. The brain requires continuous supply of oxygen and glucose to meet the needs of energy requirement as it does not store excess energy and derives almost all of its energy from aerobic oxidation of glucose. Hence brain cells are vulnerable to glucose deprivation and also cannot survive more than 5–6 min without glucose. The sequence of counter-regulatory response will play significant role when the blood glucose levels fall below 70 mg/dl to protect the brain from further deterioration of effects of hypoglycemia.

Decline in Blood glucose levels below the physiological range may trigger hierarchically organized sequence of responses in the non-diabetic individual [21, 22]. It includes release of neuroendocrine hormones or counter-regulatory or anti-insulin hormones, stimulation of the autonomic nervous system (ANS), and manifestation of neurogenic and neuroglycopenic symptoms. Pancreatic beta cells suppressed the insulin secretion when blood glucose levels declines within the physiological range results in reduction of peripheral glucose uptake and increase in hepatic glucose production to prevent true hypoglycemia. In further, declining intra-islet insulin plays an important role for the glucagon response to hypoglycemia by increase the release of glucagon by pancreatic alpha cells [23–25] and pancreatic polypeptide from the pancreas. Similarly catecholamines such as epinephrine secreted from the adrenal medullae and norepinephrine from sympathetic postganglionic nerve terminals and adrenal medulla. Cortisol from the adrenal cortex and growth hormone from the anterior pituitary gland also triggered when blood glucose level falls. The primary physiological fast acting hormones in response to hypoglycemia are glucagon and epinephrine.

Glucagon hormones enhance endogenous glucose production by the process of glycogenolysis and gluconeogenesis and generating glucose substrates such as lactate, pyruvate, alanine, and glycerol. In addition, epinephrine also has similar effects like glucagon in increase of endogenous glucose production and inhibition of utilization of glucose in the peripheral tissue and converts the gluconeogenic pathway. It can also stimulate net renal glucose production. However inhibition of insulin secretion is the primary physiological defense against decrease blood glucose and occurs at a plasma glucose concentration of less than 80 mg/dl. The response of sympathetic nervous system against hypoglycemia is activated by both circulating catecholamines and direct innervation results in increased fat metabolism of lipolysis in adipocytes which release free fatty acid. It is estimated that 25% of the total defense against hypoglycemia by the contribution of free fatty acid. Cortisol and growth hormone are metabolic defense which are released in response to prolonged hypoglycemia; but they have modest significant effect on glucose counterregulation during acute stage. The actions of these hormones are increasing glucose

**95**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

production and restraining glucose disposal after 4 h onset of hypoglycemia. It has only 20% of counter-regulatory response compared to the action of epinephrine. If counter-regulatory mechanism fails to maintain the glucose homeostasis and blood glucose value of 3.0–3.5 mmol/l, may trigger the autonomic nervous system mediated warning symptoms such as sweating, palpitation and hunger to warn subjective awareness of hypoglycemia and provoke feeling of eating to improve blood glucose level. If not consume adequate glucose during this stage, central nervous deprives for glucose, neuroglycopenia develops and cognitive function declines. Counter-regulatory responses to hypoglycemia also referred to as glycemic thresholds and may be altered to higher plasma glucose levels following chronic hyperglycemia [26] or to lower plasma glucose levels following repeated hypoglycemia [27–29]. On the whole, the magnitude of counter-regulatory function is decrease

The glycemic threshold has a dynamic and significant role in the activation of counter-regulatory physiological response against the low plasma glucose level [20]. Though the individuals have increased level of glycated hemoglobin (HbA1C) may perceive the symptoms of hypoglycemia at higher blood individuals who undergo intensive glucose level with diabetes [31]. It means sudden and rapid declines of blood glucose from higher level to a lower but not too low and at this level brain started reacting to change and release of counter-regulatory hormones. This phenomenon is called "**relative hypoglycemia**" and it is self-limiting. Brain will usually takes 2–4 weeks to readjust and to improve that relatively reduced circulat-

In contrast, among diabetic patients who are on the intensive treatment of control of plasma glucose level may not perceive hypoglycemia until their plasma glucose is considerably lower than the normal physiological glycemic thresholds [33, 35]. The changes in this glycemic control are highly influenced chronically by persistent hyperglycemia and acutely by antecedent hypoglycemia [12, 35–38]. **Antecedent hypoglycemia** is a condition caused by hypoglycemia itself which impairs and reduces the reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia. An experimental study found that there is a significant reduction in glucagon, epinephrine, cortisol, pancreatic polypeptide responses to next-day of hypoglycemia among antecedent hypoglycemic patients who experienced two episodes with the blood glucose level of 50 mg/dl. It was also demonstrated that antecedent hypoglycemia reduced the neurogenic and neuroglycopenic symptom responses [28]. In later another study investigated the responses of metabolic and neuroendocrine on the effect of morning hypoglycemia to subsequent afternoon hypoglycemia. The findings revealed that only one prolonged, moderate hypoglycemic episode can also blunt the substantial changes of physiological counter-regulatory defense and the neurogenic and neuroglycopenic

This impaired counter-regulatory responses otherwise called as "**hypoglycemiaassociated autonomic failure**" causes reduced neuroendocrine counter-regulatory responses to hypoglycemia and lowered glycemic thresholds for activation of physiological defenses against hypoglycemia, which together lead to a condition called **hypoglycemic unawareness**. During this stage, because of failure to trigger the epinephrine secretion against severe drop in blood sugar, the individuals unaware of hypoglycemic symptoms of sweating, palpitation, anxiety generated by epinephrine. These symptoms are very significantly important to warn the individuals of the

with age 18 and is more obvious in male than in female [30].

**6. Hypoglycemia and glycemic threshold**

symptom response to subsequent hypoglycemia [39].

ing glucose levels [27, 31–34].

#### *Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

*Blood Glucose Levels*

• Transcription errors

hyperkalemia and glucose and

• insulin infusion to blood glucose control

**5. Physiology of glucose counter-regulation**

further deterioration of effects of hypoglycemia.

are glucagon and epinephrine.

• Confusing the insulin strength with the dose

• Inappropriately withdrawing insulin using a standard insulin syringe

• Confusion between the prescription of a glucose and insulin infusion for

The most metabolically active organ is brain and it is the first organ affected by lower blood glucose level. The brain requires continuous supply of oxygen and glucose to meet the needs of energy requirement as it does not store excess energy and derives almost all of its energy from aerobic oxidation of glucose. Hence brain cells are vulnerable to glucose deprivation and also cannot survive more than 5–6 min without glucose. The sequence of counter-regulatory response will play significant role when the blood glucose levels fall below 70 mg/dl to protect the brain from

Decline in Blood glucose levels below the physiological range may trigger hierarchically organized sequence of responses in the non-diabetic individual [21, 22]. It includes release of neuroendocrine hormones or counter-regulatory or anti-insulin hormones, stimulation of the autonomic nervous system (ANS), and manifestation of neurogenic and neuroglycopenic symptoms. Pancreatic beta cells suppressed the insulin secretion when blood glucose levels declines within the physiological range results in reduction of peripheral glucose uptake and increase in hepatic glucose production to prevent true hypoglycemia. In further, declining intra-islet insulin plays an important role for the glucagon response to hypoglycemia by increase the release of glucagon by pancreatic alpha cells [23–25] and pancreatic polypeptide from the pancreas. Similarly catecholamines such as epinephrine secreted from the adrenal medullae and norepinephrine from sympathetic postganglionic nerve terminals and adrenal medulla. Cortisol from the adrenal cortex and growth hormone from the anterior pituitary gland also triggered when blood glucose level falls. The primary physiological fast acting hormones in response to hypoglycemia

Glucagon hormones enhance endogenous glucose production by the process of glycogenolysis and gluconeogenesis and generating glucose substrates such as lactate, pyruvate, alanine, and glycerol. In addition, epinephrine also has similar effects like glucagon in increase of endogenous glucose production and inhibition of utilization of glucose in the peripheral tissue and converts the gluconeogenic pathway. It can also stimulate net renal glucose production. However inhibition of insulin secretion is the primary physiological defense against decrease blood glucose and occurs at a plasma glucose concentration of less than 80 mg/dl. The response of sympathetic nervous system against hypoglycemia is activated by both circulating catecholamines and direct innervation results in increased fat metabolism of lipolysis in adipocytes which release free fatty acid. It is estimated that 25% of the total defense against hypoglycemia by the contribution of free fatty acid. Cortisol and growth hormone are metabolic defense which are released in response to prolonged hypoglycemia; but they have modest significant effect on glucose counterregulation during acute stage. The actions of these hormones are increasing glucose

**94**

production and restraining glucose disposal after 4 h onset of hypoglycemia. It has only 20% of counter-regulatory response compared to the action of epinephrine.

If counter-regulatory mechanism fails to maintain the glucose homeostasis and blood glucose value of 3.0–3.5 mmol/l, may trigger the autonomic nervous system mediated warning symptoms such as sweating, palpitation and hunger to warn subjective awareness of hypoglycemia and provoke feeling of eating to improve blood glucose level. If not consume adequate glucose during this stage, central nervous deprives for glucose, neuroglycopenia develops and cognitive function declines. Counter-regulatory responses to hypoglycemia also referred to as glycemic thresholds and may be altered to higher plasma glucose levels following chronic hyperglycemia [26] or to lower plasma glucose levels following repeated hypoglycemia [27–29]. On the whole, the magnitude of counter-regulatory function is decrease with age 18 and is more obvious in male than in female [30].

#### **6. Hypoglycemia and glycemic threshold**

The glycemic threshold has a dynamic and significant role in the activation of counter-regulatory physiological response against the low plasma glucose level [20]. Though the individuals have increased level of glycated hemoglobin (HbA1C) may perceive the symptoms of hypoglycemia at higher blood individuals who undergo intensive glucose level with diabetes [31]. It means sudden and rapid declines of blood glucose from higher level to a lower but not too low and at this level brain started reacting to change and release of counter-regulatory hormones. This phenomenon is called "**relative hypoglycemia**" and it is self-limiting. Brain will usually takes 2–4 weeks to readjust and to improve that relatively reduced circulating glucose levels [27, 31–34].

In contrast, among diabetic patients who are on the intensive treatment of control of plasma glucose level may not perceive hypoglycemia until their plasma glucose is considerably lower than the normal physiological glycemic thresholds [33, 35]. The changes in this glycemic control are highly influenced chronically by persistent hyperglycemia and acutely by antecedent hypoglycemia [12, 35–38]. **Antecedent hypoglycemia** is a condition caused by hypoglycemia itself which impairs and reduces the reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia. An experimental study found that there is a significant reduction in glucagon, epinephrine, cortisol, pancreatic polypeptide responses to next-day of hypoglycemia among antecedent hypoglycemic patients who experienced two episodes with the blood glucose level of 50 mg/dl. It was also demonstrated that antecedent hypoglycemia reduced the neurogenic and neuroglycopenic symptom responses [28]. In later another study investigated the responses of metabolic and neuroendocrine on the effect of morning hypoglycemia to subsequent afternoon hypoglycemia. The findings revealed that only one prolonged, moderate hypoglycemic episode can also blunt the substantial changes of physiological counter-regulatory defense and the neurogenic and neuroglycopenic symptom response to subsequent hypoglycemia [39].

This impaired counter-regulatory responses otherwise called as "**hypoglycemiaassociated autonomic failure**" causes reduced neuroendocrine counter-regulatory responses to hypoglycemia and lowered glycemic thresholds for activation of physiological defenses against hypoglycemia, which together lead to a condition called **hypoglycemic unawareness**. During this stage, because of failure to trigger the epinephrine secretion against severe drop in blood sugar, the individuals unaware of hypoglycemic symptoms of sweating, palpitation, anxiety generated by epinephrine. These symptoms are very significantly important to warn the individuals of the

lowering blood glucose level. Same scenario happened in intensively treated type 1 and type 2 diabetic individuals due to shifting of glycemic threshold to lower plasma glucose level [33, 39–42] which further limits the efforts to attain euglycemia [37, 38].

#### **7. Clinical manifestations of hypoglycemia**

Hypoglycemic signs and symptoms (**Table 3**) may occur unexpectedly and suddenly depends on the blood glucose level and may also vary from one person to another. The hyperglycemic individuals who have blood glucose level with 200 mg/dl or greater may feel adrenergic hypoglycemic symptoms when blood glucose suddenly falls to 120 mg/dl or less. Whereas a person with usual blood glucose levels in the low range may not experience symptoms when blood glucose slowly drops under 50 mg/dl and also patients who have had diabetes for many years have decreased hormonal (adrenergic) response to hypoglycemia.

Hypoglycemic symptoms may manifest as neurogenic (autonomic) symptoms and cholinergic-mediated symptoms. Low blood glucose level triggered the neurogenic symptoms by activating the autonomic nervous system which releases the catecholamines (norepinephrine and epinephrine) from the adrenal medullae and acetylcholine from postsynaptic sympathetic nerve endings. Elevated epinephrine levels leads the symptoms and signs of shakiness, palpitations, sweating, nervousness, anxiety, pupil dilation, dry mouth, pallor. The cholinergic-mediated symptoms are hunger, diaphoresis and paresthesia. However, only 20% of the total neurogenic symptom was found during hypoglycemia among epinephrine infusion in intensively and conventionally treated euglycemic type 1 diabetic individuals which indicates that the symptoms of hypoglycemic is multifocal and is mainly araised from efferent pathways of central nervous system [43].

Neuroglycopenic symptoms occur as a result of deprivation of glucose in the brain cells during hypoglycemia. Neuroglycopenic symptoms are very difficult to perceive by an individual rather it is most often recognized by family members, friends and bystanders. These symptoms include irritability, confusion, aphasia, paresthesias, ataxia, headache and the most severe symptoms are seizures stupor, coma, and even death. It can also include transient focal neurological deficits such as diplopia, hemiparesis.


**97**

**1 diabetes**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

are reproduced in **Table 4**.

*Edinburgh hypoglycemia scale.*

Sweating Palpitations Shaking Hunger

**Table 4.**

**8. Levels of hypoglycemia**

**8.1 Level I (mild) hypoglycemia**

nervous system is stimulation.

**8.2 Level II (moderate) hypoglycemia**

**8.3 Level III (severe hypoglycemia)**

to impaired function of central nervous system.

Neurogenic and neuroglycopenic symptoms are manifested by the activation of the sympatho-adrenal system and brain's glucose deprivation. The brain is continuously depends on a circulating glucose for energy and for cognitive function. If blood glucose levels fall causes cognitive dysfunction [44]. The 11 most commonly reported symptoms were used to form the Edinburgh Hypoglycemia Scale [45] and

Headache Nausea

**Autonomic Neuroglycopenic General malaise**

Confusion Drowsiness Odd behavior Speech difficulty Incoordination

According to the blood glucose level and manifestation of signs and symptoms in response to low blood glucose level, hypoglycemia can be categorized into Level I,

The range of blood glucose level is 54–70 mg/dl. Symptoms include tremor, palpitations, tachycardia, nervousness, sweating and hunger due to sympathetic

The range of blood glucose level is 40–54 mg/dl. It may produce confusion, irritation, inability to concentrate, headache, lightheadedness, memory loss, numbness of the lips and tongue, slurred speech, lack of coordination, emotional changes, drowsiness, and double vision, or any combination of these symptoms due

In severe hypoglycemia, the blood glucose level is less than 40 mg/dl. Central nervous system function is impaired further. Symptoms may include disoriented behavior, seizures, stupor, or loss of consciousness. During this stage they need help from another as they unable to function because of physical and mental changes.

**9. Mechanisms of counter-regulatory responses to hypoglycemia in type** 

Type 1 diabetes mellitus is otherwise called insulin dependent diabetes mellitus which occur due to little production of insulin or no insulin from pancreatic betacells characterized by hyperglycemia and its associated symptoms. The treatment include for the management of diabetes mellitus is insulin, diet and exercise and

Level II and Level III or mild, moderate and severe hypoglycemia.

**Table 3.** *Signs and symptoms of hypoglycemia.*


#### **Table 4.**

*Blood Glucose Levels*

lowering blood glucose level. Same scenario happened in intensively treated type 1 and type 2 diabetic individuals due to shifting of glycemic threshold to lower plasma glucose level [33, 39–42] which further limits the efforts to attain euglycemia [37, 38].

Hypoglycemic signs and symptoms (**Table 3**) may occur unexpectedly and suddenly depends on the blood glucose level and may also vary from one person to another. The hyperglycemic individuals who have blood glucose level with 200 mg/dl or greater may feel adrenergic hypoglycemic symptoms when blood glucose suddenly falls to 120 mg/dl or less. Whereas a person with usual blood glucose levels in the low range may not experience symptoms when blood glucose slowly drops under 50 mg/dl and also patients who have had diabetes for many years have decreased

Hypoglycemic symptoms may manifest as neurogenic (autonomic) symptoms and cholinergic-mediated symptoms. Low blood glucose level triggered the neurogenic symptoms by activating the autonomic nervous system which releases the catecholamines (norepinephrine and epinephrine) from the adrenal medullae and acetylcholine from postsynaptic sympathetic nerve endings. Elevated epinephrine levels leads the symptoms and signs of shakiness, palpitations, sweating, nervousness, anxiety, pupil dilation, dry mouth, pallor. The cholinergic-mediated symptoms are hunger, diaphoresis and paresthesia. However, only 20% of the total neurogenic symptom was found during hypoglycemia among epinephrine infusion in intensively and conventionally treated euglycemic type 1 diabetic individuals which indicates that the symptoms of hypoglycemic is multifocal and is mainly

Neuroglycopenic symptoms occur as a result of deprivation of glucose in the brain cells during hypoglycemia. Neuroglycopenic symptoms are very difficult to perceive by an individual rather it is most often recognized by family members, friends and bystanders. These symptoms include irritability, confusion, aphasia, paresthesias, ataxia, headache and the most severe symptoms are seizures stupor, coma, and even death. It can also include transient focal neuro-

> Blurred vision Difficulty speaking Feeling faint Difficulty thinking Confusion Dizziness Feeling drowsy Irritability

Transient Focal Neurological Deficit occasionally

**7. Clinical manifestations of hypoglycemia**

hormonal (adrenergic) response to hypoglycemia.

araised from efferent pathways of central nervous system [43].

**Autonomic symptoms Neuroglycopenic symptoms**

**Autonomic signs Neuroglycopenic signs**

logical deficits such as diplopia, hemiparesis.

**96**

**Table 3.**

Sweating Tingling Trembling Feeling shaky Feeling hungry Palpitations Anxiety

Tachycardia

Pallor Diaphoresis Mydriasis

Increased systolic blood pressure

*Signs and symptoms of hypoglycemia.*

*Edinburgh hypoglycemia scale.*

Neurogenic and neuroglycopenic symptoms are manifested by the activation of the sympatho-adrenal system and brain's glucose deprivation. The brain is continuously depends on a circulating glucose for energy and for cognitive function. If blood glucose levels fall causes cognitive dysfunction [44]. The 11 most commonly reported symptoms were used to form the Edinburgh Hypoglycemia Scale [45] and are reproduced in **Table 4**.

#### **8. Levels of hypoglycemia**

According to the blood glucose level and manifestation of signs and symptoms in response to low blood glucose level, hypoglycemia can be categorized into Level I, Level II and Level III or mild, moderate and severe hypoglycemia.

#### **8.1 Level I (mild) hypoglycemia**

The range of blood glucose level is 54–70 mg/dl. Symptoms include tremor, palpitations, tachycardia, nervousness, sweating and hunger due to sympathetic nervous system is stimulation.

#### **8.2 Level II (moderate) hypoglycemia**

The range of blood glucose level is 40–54 mg/dl. It may produce confusion, irritation, inability to concentrate, headache, lightheadedness, memory loss, numbness of the lips and tongue, slurred speech, lack of coordination, emotional changes, drowsiness, and double vision, or any combination of these symptoms due to impaired function of central nervous system.

#### **8.3 Level III (severe hypoglycemia)**

In severe hypoglycemia, the blood glucose level is less than 40 mg/dl. Central nervous system function is impaired further. Symptoms may include disoriented behavior, seizures, stupor, or loss of consciousness. During this stage they need help from another as they unable to function because of physical and mental changes.

#### **9. Mechanisms of counter-regulatory responses to hypoglycemia in type 1 diabetes**

Type 1 diabetes mellitus is otherwise called insulin dependent diabetes mellitus which occur due to little production of insulin or no insulin from pancreatic betacells characterized by hyperglycemia and its associated symptoms. The treatment include for the management of diabetes mellitus is insulin, diet and exercise and

lifestyle modification. Insulin helps to convert the glucose into glycogen and store in the liver and muscles. If there is an imbalance between the insulin administration and food intake leads to hypoglycemia. Physiologically glucagon will be secreted by the pancreatic alpha-cells to convert the stored glycogen into glucose or from non-carbohydrate substances. However in patients with type 1 diabetes for more than years epinephrine is main physiological defense in response to hypoglycemia because glucagon secretory response to hypoglycemia is irreversibly lost. In later, epinephrine response to hypoglycemia also impaired unfortunately among patients with type 1 diabetes undergoing intensive treatment of insulin and at greater risk for recurrent hypoglycemia [46, 47]. There is more than 50% reduction in counterregulatory responses toward the future hypoglycemia due to repeated attack of hypoglycemia which results in vicious cycle of iatrogenic hypoglycemia-associated autonomic failure and also subsequent hypoglycemia may also leads to antecedent hypoglycemia. Even short durations 20 minutes of antecedent hypoglycemia can produce significant impairment in counter-regulatory responses and also two episodes of hypoglycemia of 70 mg/dl can also blunt subsequent counter-regulatory responses by ∼30% in men [48]. Patient may experience severe and significant clinical consequences due to reduced adrenergic sensitivity of poor tissue responsive to circulating epinephrine and deficient responses of glucagon with reduction in ANS counter-regulatory responses. These patients also had reduced β-adrenergic sensitivity compared to patients with normal counter-regulatory responses to hypoglycemia and healthy control subjects [49] and had reduced whole-body tissue sensitivity to epinephrine, which was exacerbated by intensive glycemic control. This reduced tissue responsiveness to epinephrine is an additional contributor to the syndrome of hypoglycemia-associated autonomic failure and reduced tissue sensitivity to epinephrine resulted in decrease endogenous glucose production and less inhibition of insulin-stimulated glucose uptake. Despite with persistent blunted epinephrine response to hypoglycemia, hypoglycemic symptom and β-adrenergic sensitivity responses increase [50] to restore the endocrine and autonomic function. Although controversial, other studies have also stated that with strict avoidance of antecedent hypoglycemia some or all of the features of hypoglycemia-associated autonomic failure can be reversed [51–53].

#### **9.1 Mechanisms of counter-regulatory responses to hypoglycemia in type 2 diabetes**

Type 2 diabetes mellitus is a heterogeneous group of disease caused by inadequate secretion of insulin or improper utilization of secreted insulin or both. It may the affect all groups of people from children to older adults. Children are more commonly affected nowadays due to rise in childhood obesity. Treatment regime includes diet, exercise, oral hypoglycemic agents, glucagon like peptide-1 analogs, insulin, or combination of these and varies depending on the response to treatment and progressive β-cell failure [54]. The symptoms of hypoglycemia associated autonomic failure among type 2 diabetes depends on age, treatment modality (diet versus oral hypoglycemic agents versus insulin), comorbidity, body fat composition, metabolic control, and the presence of diabetic neuropathies [54, 55]. However, neuroendocrine contributes in glycemic responses to hypoglycemia in advanced type 2 diabetes. The glucagon response to low blood glucose level was also absent in advanced insulin-treated type 2 diabetes. Autonomic and symptomatic responses by glycemic threshold to hypoglycemia were also altered to lower plasma glucose concentrations by recent antecedent hypoglycemia. Hence, the risk for hypoglycemia-associated autonomic failure was high in advanced type 2 diabetes as like those with type 1 diabetes and leads to harmful cycle of recurrent iatrogenic hypoglycemia [46, 55].

**99**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

**10.1 Fasting (postabsorptive) hypoglycemia**

**10.3 Postprandial (reactive) hypoglycemia**

**10.4 Exercise-induced hypoglycemia**

Fanconi-Bickel syndrome.

**10.2 Patients with GSD**

intolerance.

β cells.

**10. Inborn errors of metabolism causing hypoglycemia**

postprandial hypoglycemia, and exercise-induced hypoglycemia.

Non-diabetic hypoglycemia also results from inborn errors of metabolism. Such hypoglycemia most commonly occurs in infancy but can also occur in adulthood. Cases in adults can be classified into those resulting in fasting hypoglycemia,

It is rare; disorders of glycogenolysis can result in fasting hypoglycemia. These

Type 1 and 3 characteristically have high blood lactate levels before and after meals, respectively. Both groups have hypertriglyceridemia, but ketones are high in GSD type 3. Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects can include (1) defects in the carnitine cycle; (2) fatty-acid β-oxidation disorders; (3) electron transfer disturbances; and (4) ketogenesis disorders. Finally, defects in gluconeogenesis (fructose-1, 6-biphosphatase) have

Inborn errors of metabolism resulting in postprandial hypoglycemia are also rare. These errors include (1) glucokinase, SUR1, and Kir6.2 potassium channel mutations; (2) congenital disorders of glycosylation; and (3) inherited fructose

Exercise-induced hypoglycemia, by definition, follows exercise. It results in hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in

Hypoglycemia caused by endogenous hyperinsulinism due to functional β-cell disorders, insulinoma, or the insulin autoimmune syndrome is called as accidental, surreptitious, or malicious hypoglycemia. It may also occur by accidental administration of insulin, or accidental ingestion of an insulin secretagogue such as sulfonylurea because ingestion of an insulin secretagogue causes hypoglycemia with increased C-peptide levels and hypoglycemia caused by exogenous insulin with

disorders include glycogen storage disease (GSD) of types 0, 1, 3, and 4 and

been reported to result in recurrent hypoglycemia and lactic acidosis.

**11. Accidental, surreptitious, or malicious hypoglycemia**

decrease C-peptide levels reflecting suppression of insulin secretion.

**12. Assessment and diagnostic methods**

• History collection

• Physical examination

*Blood Glucose Levels*

autonomic failure can be reversed [51–53].

**diabetes**

**9.1 Mechanisms of counter-regulatory responses to hypoglycemia in type 2** 

secretion of insulin or improper utilization of secreted insulin or both. It may the affect all groups of people from children to older adults. Children are more commonly affected nowadays due to rise in childhood obesity. Treatment regime includes diet, exercise, oral hypoglycemic agents, glucagon like peptide-1 analogs, insulin, or combination of these and varies depending on the response to treatment and progressive β-cell failure [54]. The symptoms of hypoglycemia associated autonomic failure among type 2 diabetes depends on age, treatment modality (diet versus oral hypoglycemic agents versus insulin), comorbidity, body fat composition, metabolic control, and the presence of diabetic neuropathies [54, 55]. However, neuroendocrine contributes in glycemic responses to hypoglycemia in advanced type 2 diabetes.

The glucagon response to low blood glucose level was also absent in advanced insulin-treated type 2 diabetes. Autonomic and symptomatic responses by glycemic threshold to hypoglycemia were also altered to lower plasma glucose concentrations by recent antecedent hypoglycemia. Hence, the risk for hypoglycemia-associated autonomic failure was high in advanced type 2 diabetes as like those with type 1 diabetes and leads to harmful cycle of recurrent iatrogenic hypoglycemia [46, 55].

Type 2 diabetes mellitus is a heterogeneous group of disease caused by inadequate

lifestyle modification. Insulin helps to convert the glucose into glycogen and store in the liver and muscles. If there is an imbalance between the insulin administration and food intake leads to hypoglycemia. Physiologically glucagon will be secreted by the pancreatic alpha-cells to convert the stored glycogen into glucose or from non-carbohydrate substances. However in patients with type 1 diabetes for more than years epinephrine is main physiological defense in response to hypoglycemia because glucagon secretory response to hypoglycemia is irreversibly lost. In later, epinephrine response to hypoglycemia also impaired unfortunately among patients with type 1 diabetes undergoing intensive treatment of insulin and at greater risk for recurrent hypoglycemia [46, 47]. There is more than 50% reduction in counterregulatory responses toward the future hypoglycemia due to repeated attack of hypoglycemia which results in vicious cycle of iatrogenic hypoglycemia-associated autonomic failure and also subsequent hypoglycemia may also leads to antecedent hypoglycemia. Even short durations 20 minutes of antecedent hypoglycemia can produce significant impairment in counter-regulatory responses and also two episodes of hypoglycemia of 70 mg/dl can also blunt subsequent counter-regulatory responses by ∼30% in men [48]. Patient may experience severe and significant clinical consequences due to reduced adrenergic sensitivity of poor tissue responsive to circulating epinephrine and deficient responses of glucagon with reduction in ANS counter-regulatory responses. These patients also had reduced β-adrenergic sensitivity compared to patients with normal counter-regulatory responses to hypoglycemia and healthy control subjects [49] and had reduced whole-body tissue sensitivity to epinephrine, which was exacerbated by intensive glycemic control. This reduced tissue responsiveness to epinephrine is an additional contributor to the syndrome of hypoglycemia-associated autonomic failure and reduced tissue sensitivity to epinephrine resulted in decrease endogenous glucose production and less inhibition of insulin-stimulated glucose uptake. Despite with persistent blunted epinephrine response to hypoglycemia, hypoglycemic symptom and β-adrenergic sensitivity responses increase [50] to restore the endocrine and autonomic function. Although controversial, other studies have also stated that with strict avoidance of antecedent hypoglycemia some or all of the features of hypoglycemia-associated

**98**

### **10. Inborn errors of metabolism causing hypoglycemia**

Non-diabetic hypoglycemia also results from inborn errors of metabolism. Such hypoglycemia most commonly occurs in infancy but can also occur in adulthood. Cases in adults can be classified into those resulting in fasting hypoglycemia, postprandial hypoglycemia, and exercise-induced hypoglycemia.

#### **10.1 Fasting (postabsorptive) hypoglycemia**

It is rare; disorders of glycogenolysis can result in fasting hypoglycemia. These disorders include glycogen storage disease (GSD) of types 0, 1, 3, and 4 and Fanconi-Bickel syndrome.

#### **10.2 Patients with GSD**

Type 1 and 3 characteristically have high blood lactate levels before and after meals, respectively. Both groups have hypertriglyceridemia, but ketones are high in GSD type 3. Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects can include (1) defects in the carnitine cycle; (2) fatty-acid β-oxidation disorders; (3) electron transfer disturbances; and (4) ketogenesis disorders. Finally, defects in gluconeogenesis (fructose-1, 6-biphosphatase) have been reported to result in recurrent hypoglycemia and lactic acidosis.

#### **10.3 Postprandial (reactive) hypoglycemia**

Inborn errors of metabolism resulting in postprandial hypoglycemia are also rare. These errors include (1) glucokinase, SUR1, and Kir6.2 potassium channel mutations; (2) congenital disorders of glycosylation; and (3) inherited fructose intolerance.

#### **10.4 Exercise-induced hypoglycemia**

Exercise-induced hypoglycemia, by definition, follows exercise. It results in hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in β cells.

#### **11. Accidental, surreptitious, or malicious hypoglycemia**

Hypoglycemia caused by endogenous hyperinsulinism due to functional β-cell disorders, insulinoma, or the insulin autoimmune syndrome is called as accidental, surreptitious, or malicious hypoglycemia. It may also occur by accidental administration of insulin, or accidental ingestion of an insulin secretagogue such as sulfonylurea because ingestion of an insulin secretagogue causes hypoglycemia with increased C-peptide levels and hypoglycemia caused by exogenous insulin with decrease C-peptide levels reflecting suppression of insulin secretion.

### **12. Assessment and diagnostic methods**


**Whipple triad** is the clinical presentation of pancreatic insulinoma and consists of: fasting hypoglycemia (<50 mg/dl), symptoms of hypoglycemia, immediate relief of symptoms after the administration of IV glucose.

#### **13. Management of hypoglycemia**

The aim of the treatment includes correction of glucose deficiency, prevent the complication associated with hypoglycemia and treat the underlying the cause. Treat the patient in the emergency department as shown in the **Figure 1**.


**101**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

70 mg/dl

**Figure 1.**

repeated up to 1–3 times

glycemia in later hours.

especially in type 1 diabetes mellitus.

*Schematic representation of emergency management of hypoglycemia.*

sulfonylurea-induced hypoglycemia.

• Identify and treat the underlying cause

• Assessment of glasgow coma scale

• Monitor airway, breathing, circulation

• Constant monitoring of blood glucose level

**13.1 Management of hypoglycemia in the unconscious patient**

• Administer 1 g of glucagon subcutaneously or intravenously

• Administer 50% dextrose in 25–50 mL of water intravenously

• Instruct the patient to eat protein and carbohydrate containing snack to maintain their blood glucose after 60 min if the blood glucose is higher than

• Treatment is repeated with 15 g of carbohydrates if glucose level is remains less than 70 mg/dl after the initial intake of 15 g of glucose. It may be probably

• Instruct the patient to avoid adding more table sugar to juice, even "unsweetened" juice, which may cause a sudden increase in glucose, resulting in hyper-

• Administer parenteral therapy with 25% dextrose if unable to take oral foods

• The somatostatin analog octreotide can be used to suppress insulin secretion in

• Administer inj. glucagon 1.0 mg subcutaneous/intramuscular can be used

• Check for blood glucose 15 min later.

#### *Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

#### **Figure 1.**

*Blood Glucose Levels*

• Insulin

• C-peptide

• Proinsulin

• Diagnostic investigation: It includes

• Antibodies for insulin and its receptors

• cortisol and thyroid levels, growth hormone level

relief of symptoms after the administration of IV glucose.

• History collection and physical examination

• Assess the mental status of the client

• Check for blood glucose 15 min later.

• Access intravenous line if needed

• Monitor blood glucose level

• Check the blood glucose—capillary blood glucose

**Whipple triad** is the clinical presentation of pancreatic insulinoma and consists

The aim of the treatment includes correction of glucose deficiency, prevent the complication associated with hypoglycemia and treat the underlying the cause. Treat the patient in the emergency department as shown in the **Figure 1**.

• Administer 15 g of fast acting glucose in the form of glucose tablets or glucose containing fluids, candy or food. For, e.g., three or four commercially prepared glucose tablets; 4–6 oz. of fruit juice or regular soda, 6–10 hard candies, 2–3 tsp. of sugar or honey is appropriate if the patient is able to take orally

of: fasting hypoglycemia (<50 mg/dl), symptoms of hypoglycemia, immediate

• Sulfonylurea and meglitinide screen

• Complete blood count

• Beta-hydroxybutyrate

• Electrolytes, BUN/Cr, UA

• Other tests: CT and MRI

**13. Management of hypoglycemia**

• liver function tests,

• Glucose—fasting and postprandial blood glucose

**100**

*Schematic representation of emergency management of hypoglycemia.*


#### **13.1 Management of hypoglycemia in the unconscious patient**


#### **13.2 Management of non-diabetic hypoglycemia**

Depend on the underlying etiology


#### **13.3 Health education**


**103**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

etc.

identity card.

**Acknowledgements**

**Conflict of interest**

**Author details**

Thenmozhi Paluchamy

**14. Conclusion**

ticularly that caused by a sulfonylurea.

• Regular check-up and follow-up care.

expiry date and replacing the used content in the kit.

their hypoglycemia management plan while caring the clients.

Saveetha College of Nursing, SIMATS, Chennai, Tamil Nadu, India

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: thenmozhi.sethu@gmail.com

opportunity to write the chapter on Hypoglycemia.

The author declares no conflict of interest.

provided the original work is properly cited.

• Intravenous glucose is the preferable treatment of severe hypoglycemia, par-

• Keeping the hypo box hypoglycemic kit which contains glucose, glucagon, juice,

• Instructing the family members and care givers about usage this kit, check for

• Always carry the sweetener which contains easily absorbable simple sugar and

Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment. This chapter emphasis on causes and risk factors of hypoglycemia, recognition of symptoms of hypoglycemia, glucose regulatory and counter regulatory mechanism, management and prevention of hypoglycemia thereby prevent the potential complications of hypoglycemia. Health care professionals have a major role in educating clients with diabetes mellitus about hypoglycemia and to follow

The author would like to thank the IntechOpen publishers for offering me an


#### **14. Conclusion**

*Blood Glucose Levels*

tumor.

**13.3 Health education**

agent.

for medication and/or insulin.

• Quit alcohol and smoking.

• Maintain the body weight.

• Follow medication dose regularly.

symptoms of hypoglycemia.

15 min during hypoglycemia state.

makes the blood glucose level drop.

may cause permanent brain damage.

conscious and restore normal brain function

• Discontinue the offending drugs or reduce their doses

• Replace the cortisol and growth hormone if levels are deficient.

possible and in patient with a non-tumor beta cell tumor

• Surgical, radiotherapeutic, or chemotherapeutic reduction of a non–islet cell

• Medical therapy with diazoxide or octreotide can be used if resection is not

• Consult with a dietitian to develop or adjust meal plan to maintain consistency in carbohydrates at meals by calculating grams of carbohydrates so that plan

• Self-monitoring of blood glucose to detect the episodes of hypoglycemia at the earliest. Self-monitoring of blood glucose level should give an idea of what

• Do not skip meal and balance the meal plan with insulin or oral hypoglycemic

• Avoidance of exercise while having the symptoms of hypoglycemia.

• Ingestion of carbohydrate especially rapidly absorbed glucose during the

• Remember and follow rule of 15 which means 15 g of glucose raise 50 mg/dl in

**13.2 Management of non-diabetic hypoglycemia**

Depend on the underlying etiology

• Treat the underlying critical illnesses

• Surgical resection of an insulinoma is curative

• Check the patient for regaining from the state of unconsciousness. If hypoglycemic state extends for more than 5 h results in profound hypoglycemia which

• Administer IV Mannitol and dexamethasone, IV glucose with constant glucose monitoring to necessary until regain from the state of unconsciousness to

**102**

Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment. This chapter emphasis on causes and risk factors of hypoglycemia, recognition of symptoms of hypoglycemia, glucose regulatory and counter regulatory mechanism, management and prevention of hypoglycemia thereby prevent the potential complications of hypoglycemia. Health care professionals have a major role in educating clients with diabetes mellitus about hypoglycemia and to follow their hypoglycemia management plan while caring the clients.

#### **Acknowledgements**

The author would like to thank the IntechOpen publishers for offering me an opportunity to write the chapter on Hypoglycemia.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Thenmozhi Paluchamy Saveetha College of Nursing, SIMATS, Chennai, Tamil Nadu, India

\*Address all correspondence to: thenmozhi.sethu@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: A report from the American Diabetes Association Workgroup on hypoglycemia. Diabetes Care. 2005;**28**:1245-1249

[2] Hinkle JL. Brunner and Siddarth's Textbook of Medical-Surgical Nursing. 13th ed. Philadelphia, PA: Wolters Kluwer Health Publication; 2014. pp. 862-865

[3] Metchich LN, Petit WA, Inzucchi SE. The most common type of hypoglycemia is insulin-induced hypoglycemia in diabetes. The American Journal of Medicine. 2002;**113**:317-323

[4] American Diabetes Association. Hospital admission guidelines for diabetes (position statement). Diabetes Care. 2004;**27**(Suppl. 1):S103

[5] Briscoe VJ, Davis SN. Hypoglycemia in type 1 and type 2 diabetes: Physiology, pathophysiology, and management. Clinical Diabetes. 2006;**24**(3):115-121

[6] Dajkovich G, Barkley TW Jr. Understanding insulin pump therapy. Journal of Community Health Nursing. 2015;**32**(3):131-140

[7] Cryer PE. Hypoglycemia: Pathophysiology, Diagnosis, and Treatment. New York, NY, USA: Oxford University Press; 1997

[8] The Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;**287**(19):2563-2569

[9] Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ,

et al. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A systematic review and metaanalysis of population based studies. PLoS One. 2015;**10**(6):e0126427. DOI: 10.1371/journal.pone.0126427

[10] Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in type 1 and insulintreated type 2 diabetes: A populationbased study. Diabetic Medicine. 2005;**22**(6):749-755

[11] Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, et al. The British Diabetic Association Cohort Study. II. Cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabetic Medicine. 1999;**16**:466-471

[12] The U.K. Prospective Diabetes Study Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes. Lancet. 1998;**352**:837-853

[13] Cryer PE. Glucose homeostasis and hypoglycemia. In: Larsen RP, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams Textbook of Endocrinology. 10th ed. Vol. 88. St. Louis, MO: WB Saunders; 2003. pp. 1589-1590

[14] Adler E, Paauw D. Medical myths involving diabetes. Primary Care. 2003;**30**:607-618

[15] Malouf R, Brust JC. Hypoglycemia: Causes, neurological manifestations, and outcome. Annals of Neurology. 1985;**17**:421-430

[16] Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus

**105**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

short-acting sulphonylureas. Diabetic

[25] Ter Braak E, Appelman A, Erkelens D, van Haeften T. Glibenclamide decreases glucagon release during mild hypoglycaemia. Diabetologia.

[26] Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response.

[27] Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in non-diabetics. The New England Journal of Medicine.

[28] Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes.

1998;**41**(suppl 1):A68

Diabetes. 2002;**51**:958-965

1988;**318**:1487-1492

1991;**40**:223-226

1991;**73**:995-1001

2000;**49**:65-72

2001;**18**:690-705

[29] Davis MR, Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. The Journal of Clinical Endocrinology and Metabolism.

[30] Davis SN, Fowler S, Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes.

[31] Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes. Diabetes Care. 2005;**28**:2948-2961

[32] McAuley V, Deary IJ, Freier BM. Symptoms of hypoglycemia in people with diabetes. Diabetic Medicine.

[33] Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds

[18] Kalsi A, Singh S, Taneja N, Kukal S, Mani S. Current treatments for type 2 diabetes, their side effects and possible complementary treatments. International Journal of Pharmacy and Pharmaceutical Sciences. 2015;**7**:13-18

[19] Holstein A, Egberts EH. Risk of hypoglycaemia with oral

antidiabetic agents in patients with type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes.

[20] Diedrich L, Sandoval D, Davis SN. Hypoglycemia associated autonomic failure. Clinical Autonomic Research.

Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The American Journal of Medicine.

[22] Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. The Journal of Clinical

[23] Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. The American Journal of

[24] Unger RH. The Berson memorial lecture. Insulin-glucagon relationships in the defense against hypoglycemia.

Investigation. 1987;**79**:777-781

Physiology. 1991;**260**:E67-E74

Diabetes. 1983;**32**:575-583

[21] The DCCT Research Group.

Medicine. 1999;**16**:586-590

2016;**8**:337-341

2003;**111**:405-414

2002;**12**:358-365

1991;**90**:450-459

[17] Moradi M, Mousavi S. Drug use evaluation of diabetes mellitus in non-hospitalized patients. International Journal of Pharmacy and Pharmaceutical Sciences.

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

short-acting sulphonylureas. Diabetic Medicine. 1999;**16**:586-590

[17] Moradi M, Mousavi S. Drug use evaluation of diabetes mellitus in non-hospitalized patients. International Journal of Pharmacy and Pharmaceutical Sciences. 2016;**8**:337-341

[18] Kalsi A, Singh S, Taneja N, Kukal S, Mani S. Current treatments for type 2 diabetes, their side effects and possible complementary treatments. International Journal of Pharmacy and Pharmaceutical Sciences. 2015;**7**:13-18

[19] Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes. 2003;**111**:405-414

[20] Diedrich L, Sandoval D, Davis SN. Hypoglycemia associated autonomic failure. Clinical Autonomic Research. 2002;**12**:358-365

[21] The DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The American Journal of Medicine. 1991;**90**:450-459

[22] Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. The Journal of Clinical Investigation. 1987;**79**:777-781

[23] Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. The American Journal of Physiology. 1991;**260**:E67-E74

[24] Unger RH. The Berson memorial lecture. Insulin-glucagon relationships in the defense against hypoglycemia. Diabetes. 1983;**32**:575-583

[25] Ter Braak E, Appelman A, Erkelens D, van Haeften T. Glibenclamide decreases glucagon release during mild hypoglycaemia. Diabetologia. 1998;**41**(suppl 1):A68

[26] Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes. 2002;**51**:958-965

[27] Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in non-diabetics. The New England Journal of Medicine. 1988;**318**:1487-1492

[28] Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 1991;**40**:223-226

[29] Davis MR, Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. The Journal of Clinical Endocrinology and Metabolism. 1991;**73**:995-1001

[30] Davis SN, Fowler S, Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes. 2000;**49**:65-72

[31] Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes. Diabetes Care. 2005;**28**:2948-2961

[32] McAuley V, Deary IJ, Freier BM. Symptoms of hypoglycemia in people with diabetes. Diabetic Medicine. 2001;**18**:690-705

[33] Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds

**104**

*Blood Glucose Levels*

**References**

2005;**28**:1245-1249

[1] Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: A report from the American Diabetes Association Workgroup on hypoglycemia. Diabetes Care.

et al. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A systematic review and metaanalysis of population based studies. PLoS One. 2015;**10**(6):e0126427. DOI:

10.1371/journal.pone.0126427

2005;**22**(6):749-755

1999;**16**:466-471

pp. 1589-1590

2003;**30**:607-618

1985;**17**:421-430

[10] Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in type 1 and insulintreated type 2 diabetes: A populationbased study. Diabetic Medicine.

[11] Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, et al. The British Diabetic Association Cohort Study. II. Cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabetic Medicine.

[12] The U.K. Prospective Diabetes Study Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes. Lancet. 1998;**352**:837-853

[13] Cryer PE. Glucose homeostasis and hypoglycemia. In: Larsen RP, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams Textbook of Endocrinology. 10th ed. Vol. 88. St. Louis, MO: WB Saunders; 2003.

[14] Adler E, Paauw D. Medical myths involving diabetes. Primary Care.

[15] Malouf R, Brust JC. Hypoglycemia: Causes, neurological manifestations, and outcome. Annals of Neurology.

[16] Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus

[2] Hinkle JL. Brunner and Siddarth's Textbook of Medical-Surgical Nursing. 13th ed. Philadelphia, PA: Wolters Kluwer Health Publication; 2014. pp. 862-865

[3] Metchich LN, Petit WA, Inzucchi SE. The most common type of hypoglycemia is insulin-induced

[4] American Diabetes Association. Hospital admission guidelines for diabetes (position statement). Diabetes

[5] Briscoe VJ, Davis SN. Hypoglycemia

Care. 2004;**27**(Suppl. 1):S103

in type 1 and type 2 diabetes: Physiology, pathophysiology, and management. Clinical Diabetes.

[6] Dajkovich G, Barkley TW Jr. Understanding insulin pump therapy. Journal of Community Health Nursing.

[7] Cryer PE. Hypoglycemia: Pathophysiology, Diagnosis, and Treatment. New York, NY, USA: Oxford

[8] The Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA.

[9] Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ,

2006;**24**(3):115-121

2015;**32**(3):131-140

University Press; 1997

2002;**287**(19):2563-2569

hypoglycemia in diabetes. The American Journal of Medicine. 2002;**113**:317-323

for counterregulatory hormone release. Diabetes. 1988;**37**:901-907

[34] Korzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, et al. Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care. 1998;**21**:283-290

[35] Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;**26**:1902-1912

[36] The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complication in insulindependent diabetes mellitus. The New England Journal of Medicine. 1993;**329**:977-986

[37] Cryer PE. Hypoglycemia risk reduction in type 1 diabetes. Experimental and Clinical Endocrinology & Diabetes. 2001;**109**:S412-S423

[38] Cryer PE. Current concepts: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. The New England Journal of Medicine. 2004;**350**:2272-2279

[39] Davis SN, Tate D. Effects of morning hypoglycemia on neuroendocrine and metabolic responses to subsequent afternoon hypoglycemia in normal man. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**:2043-2050

[40] Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. The Journal of Clinical Investigation. 1993;**91**:819-828

[41] Segel SA, Paramore DS, Cryer PE. Defective glucose counterregulation in type 2 diabetes (Abstract). Diabetes. 2000;**49**:A131

[42] Spyer G, Hattersley AT, MacDonald IA, Amiel S, MacLeod KM. Hypoglycaemic counterregulation at normal blood glucose concentrations in patients with well controlled type 2 diabetes. Lancet. 2000;**356**:1970-1974

[43] Aftab-Guy D, Sandoval D, Richardson MA, Tate D, Davis SN. Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes. American Journal of Physiology. Endocrinology and Metabolism. 2005;**289**:E258-E265

[44] Inkster B, Frier BM. The effects of acute hypoglycaemia on cognitive function in type 1 diabetes. The British Journal of Diabetes and Vascular Disease. 2012;**12**:221-226

[45] Deary IJ, Hepburn DA, MacLeod KM, Frier BM. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia. 1993;**36**:771-777

[46] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;**54**:3592-3598

[47] White NH, Skor A, Cryer PE, Levandoski L, Dier DM, Santiago JV. Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy. The New England Journal of Medicine. 1993;**308**:485-491

[48] Davis SN, Shavers C, Mosqueda-Garcia R, Costa F. Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes. 1997;**46**:328-1335

[49] Korytkowski MT, Mokan M, Veneman TE, Mitrakou A, Cryer PE, Gerich JE. Reduced betaadrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness. Diabetes Care. 1998;**21**:1939-1943

**107**

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

[50] Fritsche A, Stefan N, Haring H, Gerich J, Stumvoll M. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing betaadrenergic sensitivity in type 1 diabetes. Annals of Internal Medicine. 2001;**134**:729-736

[51] Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994;**344**:283-287

[52] Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Ciofetta M, Modarelli F, et al. Relative roles of insulin and hypoglycemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycemia in male and female humans. Diabetologia.

[53] Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes.

[54] de Galan BE, Hoekstra JBL. Glucose counterregulation in type 2 diabetes

[55] Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes.

mellitus. Diabetic Medicine.

Diabetes. 2002;**51**:724-732

1994;**37**:797-807

1994;**43**:1426-1434

2001;**18**:519-527

*Hypoglycemia: Essential Clinical Guidelines DOI: http://dx.doi.org/10.5772/intechopen.86994*

*Blood Glucose Levels*

Diabetes. 1988;**37**:901-907

Care. 2003;**26**:1902-1912

1993;**329**:977-986

2001;**109**:S412-S423

2004;**350**:2272-2279

[39] Davis SN, Tate D. Effects of morning hypoglycemia on neuroendocrine and metabolic responses to subsequent afternoon hypoglycemia in normal man. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**:2043-2050

[37] Cryer PE. Hypoglycemia risk reduction in type 1 diabetes. Experimental and Clinical Endocrinology & Diabetes.

[38] Cryer PE. Current concepts: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. The New England Journal of Medicine.

[40] Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. The Journal of Clinical Investigation. 1993;**91**:819-828

[41] Segel SA, Paramore DS, Cryer PE. Defective glucose counterregulation in type 2 diabetes (Abstract). Diabetes.

for counterregulatory hormone release.

[42] Spyer G, Hattersley AT,

[43] Aftab-Guy D, Sandoval D, Richardson MA, Tate D, Davis SN. Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes. American Journal of Physiology. Endocrinology and Metabolism. 2005;**289**:E258-E265

[44] Inkster B, Frier BM. The effects of acute hypoglycaemia on cognitive function in type 1 diabetes. The British Journal of Diabetes and Vascular

[45] Deary IJ, Hepburn DA, MacLeod KM, Frier BM. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia. 1993;**36**:771-777

[46] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;**54**:3592-3598

[47] White NH, Skor A, Cryer PE, Levandoski L, Dier DM, Santiago JV. Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy. The New England Journal of Medicine.

[48] Davis SN, Shavers C, Mosqueda-Garcia R, Costa F. Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans.

Diabetes. 1997;**46**:328-1335

[49] Korytkowski MT, Mokan M, Veneman TE, Mitrakou A, Cryer PE, Gerich JE. Reduced betaadrenergic sensitivity in patients with type 1

Diabetes Care. 1998;**21**:1939-1943

diabetes and hypoglycemia unawareness.

1993;**308**:485-491

Disease. 2012;**12**:221-226

MacDonald IA, Amiel S, MacLeod KM. Hypoglycaemic counterregulation at normal blood glucose concentrations in patients with well controlled type 2 diabetes. Lancet. 2000;**356**:1970-1974

[34] Korzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, et al. Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care. 1998;**21**:283-290

[35] Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes

[36] The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complication in insulindependent diabetes mellitus. The New England Journal of Medicine.

**106**

2000;**49**:A131

[50] Fritsche A, Stefan N, Haring H, Gerich J, Stumvoll M. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing betaadrenergic sensitivity in type 1 diabetes. Annals of Internal Medicine. 2001;**134**:729-736

[51] Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994;**344**:283-287

[52] Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Ciofetta M, Modarelli F, et al. Relative roles of insulin and hypoglycemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycemia in male and female humans. Diabetologia. 1994;**37**:797-807

[53] Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994;**43**:1426-1434

[54] de Galan BE, Hoekstra JBL. Glucose counterregulation in type 2 diabetes mellitus. Diabetic Medicine. 2001;**18**:519-527

[55] Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes. 2002;**51**:724-732

**109**

Section 4

Lifestyle and Metabolic

Syndrome

Section 4

## Lifestyle and Metabolic Syndrome

**111**

**Chapter 8**

**Abstract**

**1. Introduction**

fasting plasma glucose and blood pressure.

**2. Lifestyle during the month of Ramadan**

*Khalid S. Aljaloud*

The Effect of Ramadan Fasting on

The effect of Ramadan fasting on most of the metabolic syndrome (MetS) markers is still controversial. However, most of the available evidences showed positive effect on most of the MetS markers. In general, Ramadan fasting may help to reduce the risk of MetS. Nevertheless, most of the positive results seem to be impermanent and reading many variables (MetS markers) return to the previous reading after few weeks (~3–4 weeks). Therefore, intermittent fasting such as Ramadan fasting could be one of the cure alternatives especially in people with MetS, cardiovascular or metabolic diseases with considering their physician supervision. Again, more evidences are recommended to clarify the controversial

**Keywords:** Ramadan fasting, cholesterol, glucose, metabolic syndrome (MetS)

Lifestyle plays significant role in metabolic syndrome. Habitual diet, physical activity status, type of sleep—including quantity and quality—and unhealthy behaviors such as smoking, consuming alcohol, etc. may affect metabolic syndrome markers [1]. This chapter will demonstrate overview of lifestyle during the month of Ramadan including diet, physical activity and sleep. Moreover, the effects of Ramadan fasting on each metabolic syndrome (MetS) markers will be revealed including central obesity, plasma triglyceride, high density lipoprotein-cholesterol,

The month of Ramadan is a holy month in the Islamic calendar (lunar calendar

vary between 29 or 30 days) once a year. About 1.5 billion Muslims worldwide are—religiously—abstained from having any kind of food, oral intake such as medicine (unless in necessary cases) or smoking during the daylight starting from dawn to sunset. The Holy month of Ramadan retreats 11 days each year. As a result, Ramadan month moves in all seasons over time including summer season. Usually fasting time extends between 13 and 18 hours per day depending on season (spring, summer, autumn or winter) and the geographical location of the country. During the month of Ramadan, lifestyle of most Muslim people changes. In most Muslim country, people become less active during the daytime (before the sunset) compared with the nighttime (after the sunset), especially when most

Metabolic Syndrome (MetS)

issues related to the role of Ramadan fasting on MetS markers.

#### **Chapter 8**

### The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)

*Khalid S. Aljaloud*

#### **Abstract**

The effect of Ramadan fasting on most of the metabolic syndrome (MetS) markers is still controversial. However, most of the available evidences showed positive effect on most of the MetS markers. In general, Ramadan fasting may help to reduce the risk of MetS. Nevertheless, most of the positive results seem to be impermanent and reading many variables (MetS markers) return to the previous reading after few weeks (~3–4 weeks). Therefore, intermittent fasting such as Ramadan fasting could be one of the cure alternatives especially in people with MetS, cardiovascular or metabolic diseases with considering their physician supervision. Again, more evidences are recommended to clarify the controversial issues related to the role of Ramadan fasting on MetS markers.

**Keywords:** Ramadan fasting, cholesterol, glucose, metabolic syndrome (MetS)

#### **1. Introduction**

Lifestyle plays significant role in metabolic syndrome. Habitual diet, physical activity status, type of sleep—including quantity and quality—and unhealthy behaviors such as smoking, consuming alcohol, etc. may affect metabolic syndrome markers [1]. This chapter will demonstrate overview of lifestyle during the month of Ramadan including diet, physical activity and sleep. Moreover, the effects of Ramadan fasting on each metabolic syndrome (MetS) markers will be revealed including central obesity, plasma triglyceride, high density lipoprotein-cholesterol, fasting plasma glucose and blood pressure.

#### **2. Lifestyle during the month of Ramadan**

The month of Ramadan is a holy month in the Islamic calendar (lunar calendar vary between 29 or 30 days) once a year. About 1.5 billion Muslims worldwide are—religiously—abstained from having any kind of food, oral intake such as medicine (unless in necessary cases) or smoking during the daylight starting from dawn to sunset. The Holy month of Ramadan retreats 11 days each year. As a result, Ramadan month moves in all seasons over time including summer season. Usually fasting time extends between 13 and 18 hours per day depending on season (spring, summer, autumn or winter) and the geographical location of the country. During the month of Ramadan, lifestyle of most Muslim people changes. In most Muslim country, people become less active during the daytime (before the sunset) compared with the nighttime (after the sunset), especially when most

are Muslims population [2]. The reason is mainly due to their nature of life during the night as majority of them engaging in social activities with friends and family. Moreover, most of the markets and media become more vital. However, the lifestyle of some Muslims will not change greatly during Ramadan [3]. Hence, the change in habitual diet, physical activity and sleep may change the body composition and some blood markers such as cholesterol, triglyceride, glucose which may alert MetS markers.

#### **3. Diet during the month of Ramadan**

Muslims break their fasting just after sunset by having a main meal and then they may have two or three meals during the night until the dawn time. Current study found that diet did not change significantly during the month of Ramadan while comparing before or after Ramadan [2]. However, Al-barha's study recruited apparently healthy graduate and undergraduate students. Data from different studies reported that diet during the month of Ramadan varies due to the differences between Muslim population in different countries and their habitual lifestyle. Further, seasonal and weather differences may play role in the quality and quantity of the food intake as well as the diet behavior during the month of Ramadan. In a review study, 9 out of 13 publications reported either significant reduction or no significant difference in energy intake between during and pre-or-post the month of Ramadan [4–12]. Only four studies showed a significant increase in energy intake during Ramadan [13–16]. However, all of the studies in these publications use selfreport to assess the energy intake, which is known to be less accurate comparing to objective measures [17, 18]. Amount and type of food intake as well as timing are key factors in diet and its effect on body including metabolic syndrome. During the month of Ramadan, carbohydrate and fat are consumed just after sunset. Different Muslim population reported high intake of dietary fat during Ramadan which exceeded the dietary recommendations [6, 11, 19]. In contrast, some studies found no significant change in carbohydrate and protein. However, the type of carbohydrate switched from complex sugar such as bread, cereal and vegetable to more simple sugar such as sweets [20]. These changes could elevate blood parameters such as blood lipids level. Hence, it could affect the metabolic syndrome markers negatively.

#### **4. Physical activity during the month of Ramadan**

The recent guidelines of physical activity and exercise encourage people to be physically active. The recommendation has been issued for each age group such as children and adult as well as people with special conditions such as elderly, diabetics and obese individuals [21]. The changes in people lifestyle may affect health and wellbeing [3]. During Ramadan, lifestyle may change including habitual physical activity. Although some studies found that there is no significant change in physical activity levels during Ramadan comparing to pre-Ramadan [2], numerous evidences reported significant changes in physical activity levels during the month of Ramadan. Ramadan fasting has been found to affect physical activity level in different ways. Some studies indicated that habitual physical activity may change during the month of Ramadan [22, 23]. Moreover, number of previous studies has investigated the association between Ramadan fasting and physical activity in Muslim population. These studies reported that physical activity levels were

**113**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

lowered in Muslim population during the month of Ramadan [24–28]. For instant, about one-third of Saudi families reported a decrease in physical activity levels [29]. Furthermore, recent study found that Ramadan fasting is associated with decrease in physical activity levels [30]; and may causes a decline in the physical work capacity in adolescent soccer players especially cardiorespiratory fitness capability [31]. However, these evidences showed no significant change in resting metabolic rate

The reduction in physical activity and exercise may alert the metabolic syndrome markers. Several studies have shown significant association between low physical activity level and negative changes in some of the metabolic syndrome markers. Individuals with low physical activity are more likely to have negative changes in metabolic syndrome [20, 32]. More about the impact of low physical activity in MetS will be discussed later in this chapter. These results may help to understand the influence of Ramadan fasting on body composition and the charac-

Body mass, BMI and waist circumference (WC) decreased gradually, especially in the end week of Ramadan compared with the reading before Ramadan. However, most of the recent studies concluded that the slightly decrease in some body composition parameters were not significant [4, 20, 33–36]. Although some the studies reported significant reduction in body weight at the end of Ramadan, the reduction was temporary. In a recent review study, the relationship between body composition parameters (i.e. body mass, body mass index, fat percentage and waist circumference) and Ramadan fasting is elucidated. Fernando and colleagues [29] concluded that there was a significant reduction in fat percentage at the end of Ramadan compared with pre-Ramadan in overweight or obese individuals, but not in those of normal weight. Moreover, even the change in body composition during the month of Ramadan was temporary as most of the investigated body composi-

In terms of sleep pattern, working hours during the month of Ramadan—at least in some countries—are shorter for those who fast. In such countries, workers are given more time to sleep after having the last meal just before the dawn time. For this reason, people start work later in the morning (between 09:00 and 10:00 am) instead of the early morning (i.e. 07:00–08:00 am). This change could affect sleep patterns. Hence, this may affect the times they go to bed and wake up [38]. Moreover, sleep habits may change more during the daytime. In turn, the change in sleep pattern may lead to some changes in some of the physiological parameters including metabolic syndrome as well as body composition [39, 40]. In a recent review study, they found that well-organized studies that controlled sleep/wake time, sleep duration and light exposure do not influence Ramadan fasting.

Furthermore, well-designed studies showed no effect of Ramadan fasting on circadian rhythms. However, in unstable society in which they do not control for lifestyle changes, evidences have demonstrated sudden and significant delays in bedtime and wake time [41]. Controllable and uncontrollable MetS risk factors may

lead to cardiovascular and metabolic diseases as illustrated in **Figure 1**.

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

(RMR) or total energy expenditure (TEE) [30].

tion parameters return to the normal weight [37].

**6. Sleep during the month of Ramadan**

teristics of metabolic syndrome.

**5. Body composition**

#### *The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

lowered in Muslim population during the month of Ramadan [24–28]. For instant, about one-third of Saudi families reported a decrease in physical activity levels [29]. Furthermore, recent study found that Ramadan fasting is associated with decrease in physical activity levels [30]; and may causes a decline in the physical work capacity in adolescent soccer players especially cardiorespiratory fitness capability [31]. However, these evidences showed no significant change in resting metabolic rate (RMR) or total energy expenditure (TEE) [30].

The reduction in physical activity and exercise may alert the metabolic syndrome markers. Several studies have shown significant association between low physical activity level and negative changes in some of the metabolic syndrome markers. Individuals with low physical activity are more likely to have negative changes in metabolic syndrome [20, 32]. More about the impact of low physical activity in MetS will be discussed later in this chapter. These results may help to understand the influence of Ramadan fasting on body composition and the characteristics of metabolic syndrome.

#### **5. Body composition**

*Blood Glucose Levels*

alert MetS markers.

**3. Diet during the month of Ramadan**

**4. Physical activity during the month of Ramadan**

The recent guidelines of physical activity and exercise encourage people to be physically active. The recommendation has been issued for each age group such as children and adult as well as people with special conditions such as elderly, diabetics and obese individuals [21]. The changes in people lifestyle may affect health and wellbeing [3]. During Ramadan, lifestyle may change including habitual physical activity. Although some studies found that there is no significant change in physical activity levels during Ramadan comparing to pre-Ramadan [2], numerous evidences reported significant changes in physical activity levels during the month of Ramadan. Ramadan fasting has been found to affect physical activity level in different ways. Some studies indicated that habitual physical activity may change during the month of Ramadan [22, 23]. Moreover, number of previous studies has investigated the association between Ramadan fasting and physical activity in Muslim population. These studies reported that physical activity levels were

are Muslims population [2]. The reason is mainly due to their nature of life during the night as majority of them engaging in social activities with friends and family. Moreover, most of the markets and media become more vital. However, the lifestyle of some Muslims will not change greatly during Ramadan [3]. Hence, the change in habitual diet, physical activity and sleep may change the body composition and some blood markers such as cholesterol, triglyceride, glucose which may

Muslims break their fasting just after sunset by having a main meal and then they may have two or three meals during the night until the dawn time. Current study found that diet did not change significantly during the month of Ramadan while comparing before or after Ramadan [2]. However, Al-barha's study recruited apparently healthy graduate and undergraduate students. Data from different studies reported that diet during the month of Ramadan varies due to the differences between Muslim population in different countries and their habitual lifestyle. Further, seasonal and weather differences may play role in the quality and quantity of the food intake as well as the diet behavior during the month of Ramadan. In a review study, 9 out of 13 publications reported either significant reduction or no significant difference in energy intake between during and pre-or-post the month of Ramadan [4–12]. Only four studies showed a significant increase in energy intake during Ramadan [13–16]. However, all of the studies in these publications use selfreport to assess the energy intake, which is known to be less accurate comparing to objective measures [17, 18]. Amount and type of food intake as well as timing are key factors in diet and its effect on body including metabolic syndrome. During the month of Ramadan, carbohydrate and fat are consumed just after sunset. Different Muslim population reported high intake of dietary fat during Ramadan which exceeded the dietary recommendations [6, 11, 19]. In contrast, some studies found no significant change in carbohydrate and protein. However, the type of carbohydrate switched from complex sugar such as bread, cereal and vegetable to more simple sugar such as sweets [20]. These changes could elevate blood parameters such as blood lipids level. Hence, it could affect the metabolic syndrome markers

**112**

negatively.

Body mass, BMI and waist circumference (WC) decreased gradually, especially in the end week of Ramadan compared with the reading before Ramadan. However, most of the recent studies concluded that the slightly decrease in some body composition parameters were not significant [4, 20, 33–36]. Although some the studies reported significant reduction in body weight at the end of Ramadan, the reduction was temporary. In a recent review study, the relationship between body composition parameters (i.e. body mass, body mass index, fat percentage and waist circumference) and Ramadan fasting is elucidated. Fernando and colleagues [29] concluded that there was a significant reduction in fat percentage at the end of Ramadan compared with pre-Ramadan in overweight or obese individuals, but not in those of normal weight. Moreover, even the change in body composition during the month of Ramadan was temporary as most of the investigated body composition parameters return to the normal weight [37].

#### **6. Sleep during the month of Ramadan**

In terms of sleep pattern, working hours during the month of Ramadan—at least in some countries—are shorter for those who fast. In such countries, workers are given more time to sleep after having the last meal just before the dawn time. For this reason, people start work later in the morning (between 09:00 and 10:00 am) instead of the early morning (i.e. 07:00–08:00 am). This change could affect sleep patterns. Hence, this may affect the times they go to bed and wake up [38]. Moreover, sleep habits may change more during the daytime. In turn, the change in sleep pattern may lead to some changes in some of the physiological parameters including metabolic syndrome as well as body composition [39, 40]. In a recent review study, they found that well-organized studies that controlled sleep/wake time, sleep duration and light exposure do not influence Ramadan fasting.

Furthermore, well-designed studies showed no effect of Ramadan fasting on circadian rhythms. However, in unstable society in which they do not control for lifestyle changes, evidences have demonstrated sudden and significant delays in bedtime and wake time [41]. Controllable and uncontrollable MetS risk factors may lead to cardiovascular and metabolic diseases as illustrated in **Figure 1**.

**Figure 1.**

*Risk factors of MetS including controllable and uncontrollable factors that might lead to cardiovascular and metabolic diseases.*

#### **7. Metabolic syndrome**

Historically, the first time metabolic syndrome (MetS) was defined by Kylin , a Swedish physician, in 1923 [42]. He described MetS as a cluster of cardiovascular risk factors comprising of hypertension, hyperglycemia and gout. Since then, the metabolic syndrome has gradually progressed over time with definition modification. However, the core turbulences, hypertension, consisting of glucose intolerance, obesity and dyslipidemia remain the cornerstone of all diagnostic criteria. In turn, these features may develop and increase the risk of cardiovascular morbidity and mortality [43, 44]. The term "Syndrome X" was commonly used in 1980s to describe the proposed interrelationships between resistance to insulin-stimulated glucose uptake, hypertension, type 2 diabetic and cardiovascular diseases. Now, the term MetS has the International Classification of Disease (ICD-9) code 277.7. In 1990s, visceral adiposity becomes important when obesity is considered as a main factor of the insulin resistance syndrome [45]. World Health Organization (WHO) launched the first formal definition of the MetS in 1998 [46]. In 2001, the National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATPIII) issued a set of criteria based on common clinical investigations: WC, blood lipids, blood pressure and fasting glucose [47–49].

#### **8. Diagnostic criteria for MetS**

Over the years, there have been several societies attempted to issue the diagnostic criteria for metabolic syndrome [50]. In 1998, WHO is the first organization that launched the worldwide definition of MetS, which was modified by other organizations such as the European Group for the Study of Insulin Resistance (EGSIR). In 2003, the American Association of Clinical Endocrinologists (AACE) proposed

**115**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

**WHO, 1998 EGIR, 1999 NCEP:ATPIII,** 

Top 25% of the fasting insulin values among nondiabetic individuals and two of the following:

WC: 94 cm for men, 80 cm for women

Triglycerides 2.0 mmol/liter and HDLC 1.0 mg/dl

BP 140/90 mm Hg or antihypertensive medication

Fasting glucose 6.1 mmol/liter

**2001**

Three or more of the following:

WC: 40 inches for men, 35 inches for women

Triglycerides 150 mg/dl

HDL-C: 40 mg/ dl for men, 50 mg/dl for women

BP 130/85 mm

FPG 110 mg/dla

Hg

*WHR, Waist-to-hip ratio; BP, blood pressure; FPG, fasting plasma glucose. In 2003, the ADA changed the criteria* 

**AACE, 2003 IDF, 2006**

Central obesity as defined by ethnic/ racial, specific WC, and two of the following:

Triglycerides 150 mg/dl

HDL-C: 40 mg/dl for men, 50 mg/dl for women

BP 130/85 mm Hg

FPG 100 mg/dl

IGT and two or more of the following:

Triglycerides 150 mg/dl

HDL-C: 40 mg/ dl for men, 50 mg/dl for women

BP 130/85 mm

Hg

their definition. However, the definition of the cut-off for obesity was not agreed yet. **Table 1** illustrates the development stages of the MetS diagnostic criteria [52].

In this section, the role of Ramadan fasting positively affect the MetS markers including central obesity, waist circumference (WC), fasting plasma glucose (FPG) level, triglycerides (TG) level, high density lipoprotein (HDL) and blood pressure (BP), will be deliberated with recent evidences. In terms of metabolism and hormonal serum levels, Ramadan fasting may affect the metabolism of lipids, carbohydrates and proteins, as well as related hormones levels. Although there are beneficial changes in HDL and LDL levels, evidences showed that Ramadan fasting could lead to elevate the urea and uric acid which may be attributed to dehydration during the Holy month of Ramadan [23]. In the next sessions, the effect of Ramadan fasting on

Intermittent fasting during the month of Ramadan may enhance the cure from some of the MetS markers including body weight reduction. Although some evidence showed increase in some of the body composition parameters [53], Ramadan

**9. The effect of Ramadan fasting on metabolic syndrome**

metabolic syndrome markers will be elucidated with more details.

**10. The effect of Ramadan fasting on central obesity**

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

High insulin levels, IFG or IGT, and two of the following:

Abdominal obesity: WHR 0.9, BMI 30 kg/m2

37 inches

BP 140/90 mm

*for IFG tolerance from 110 to 100 mg/dl.*

*Criteria for the definitions of the metabolic syndrome.*

Lipid panel with triglycerides 150 mg/dl, HDL-C 35 mg/dl

Hg

*Source: Ref. [51].*

**Table 1.**

, WC


*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

*WHR, Waist-to-hip ratio; BP, blood pressure; FPG, fasting plasma glucose. In 2003, the ADA changed the criteria for IFG tolerance from 110 to 100 mg/dl. Source: Ref. [51].*

#### **Table 1.**

*Blood Glucose Levels*

**7. Metabolic syndrome**

**Figure 1.**

*metabolic diseases.*

pressure and fasting glucose [47–49].

**8. Diagnostic criteria for MetS**

Historically, the first time metabolic syndrome (MetS) was defined by Kylin , a Swedish physician, in 1923 [42]. He described MetS as a cluster of cardiovascular risk factors comprising of hypertension, hyperglycemia and gout. Since then, the metabolic syndrome has gradually progressed over time with definition modification. However, the core turbulences, hypertension, consisting of glucose intolerance, obesity and dyslipidemia remain the cornerstone of all diagnostic criteria. In turn, these features may develop and increase the risk of cardiovascular morbidity and mortality [43, 44]. The term "Syndrome X" was commonly used in 1980s to describe the proposed interrelationships between resistance to insulin-stimulated glucose uptake, hypertension, type 2 diabetic and cardiovascular diseases. Now, the term MetS has the International Classification of Disease (ICD-9) code 277.7. In 1990s, visceral adiposity becomes important when obesity is considered as a main factor of the insulin resistance syndrome [45]. World Health Organization (WHO) launched the first formal definition of the MetS in 1998 [46]. In 2001, the National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATPIII) issued a set of criteria based on common clinical investigations: WC, blood lipids, blood

*Risk factors of MetS including controllable and uncontrollable factors that might lead to cardiovascular and* 

Over the years, there have been several societies attempted to issue the diagnostic criteria for metabolic syndrome [50]. In 1998, WHO is the first organization that launched the worldwide definition of MetS, which was modified by other organizations such as the European Group for the Study of Insulin Resistance (EGSIR). In 2003, the American Association of Clinical Endocrinologists (AACE) proposed

**114**

*Criteria for the definitions of the metabolic syndrome.*

their definition. However, the definition of the cut-off for obesity was not agreed yet. **Table 1** illustrates the development stages of the MetS diagnostic criteria [52].

#### **9. The effect of Ramadan fasting on metabolic syndrome**

In this section, the role of Ramadan fasting positively affect the MetS markers including central obesity, waist circumference (WC), fasting plasma glucose (FPG) level, triglycerides (TG) level, high density lipoprotein (HDL) and blood pressure (BP), will be deliberated with recent evidences. In terms of metabolism and hormonal serum levels, Ramadan fasting may affect the metabolism of lipids, carbohydrates and proteins, as well as related hormones levels. Although there are beneficial changes in HDL and LDL levels, evidences showed that Ramadan fasting could lead to elevate the urea and uric acid which may be attributed to dehydration during the Holy month of Ramadan [23]. In the next sessions, the effect of Ramadan fasting on metabolic syndrome markers will be elucidated with more details.

#### **10. The effect of Ramadan fasting on central obesity**

Intermittent fasting during the month of Ramadan may enhance the cure from some of the MetS markers including body weight reduction. Although some evidence showed increase in some of the body composition parameters [53], Ramadan fasting has been found to reduce waist circumference even in apparently healthy young adults [54]. In some studies, the reported weight reduction occurred without significant changes in energy and macronutrient intake and physical activity level [4]. The reduction was interpreted as loss of body water and body fat percentage.

There is a strong recent evidence that support the effect of Ramadan fasting on reducing body fat percentage and even fat-free mass especially with obese/ overweight people. In a recent review and meta-analysis study, data obtain from 70 publications found a significant reduction in fat percentage between pre-Ramadan and post-Ramadan in overweight and obesity individuals. (−1.46 [95% confidence interval: −2.57 to −0.35]%, *P* = 0.010). However, there was no changes reported in those of normal weight (−0.41 [−1.45 to 0.63]%, *P* = 0.436). The reduction also reported in fat-free mass between pre-Ramadan and post-Ramadan. Nevertheless, the changes in body composition measurements seem to be temporary. Evidences showed that body weight body composition parameters were returned toward the pre-Ramadan measurements just after 2–5 weeks from the month of Ramadan [37]. Furthermore, it has been suggested that this decrease in body weight could be attributed to a decrease in fluid intake [34, 55–57]. Sequentially, dehydration during the month of Ramadan may cause increase in urea and uric acid which is attributed to the reduction of the glomerular filtration rate [58]. The physiological aspects that may explain the association between Ramadan fasting and body composition parameters has been investigated. For instance, plasma leptin and insulin have been found to play a key role in body weight regulation homeostasis. Leptin level send signals to the brain about the amount of energy stores which in turn, stimulates the hypothalamic centers to regulate the energy intake and energy expenditure [59]. Although an evidence showed that there is a positive association between plasma leptin and insulin levels and body fat, the elevation in plasma leptin and insulin during the month of Ramadan is probably due to the energy intake and diet behavior [14]. In sum, Ramadan fasting may help to reduce body composition including central obesity such as waist circumference. However, the reduction may not be healthy as the weight loss attribute to loss of body water. One possible reason for this greater weight loss is that people with greater BMI are due to greater glycogen stores than people of normal weight, and hence would be expected to lose more fluid in response to fasting [60], and in some cases loss of lean tissue [34] carry more body. One of the most challenges is that body composition parameters are affected by different factors including calorie intake, physical activity level, age and gender. More investigations are needed to clarify the role of Ramadan fasting on central obesity.

#### **11. The effect of Ramadan fasting on triglycerides**

In general, the role of Ramadan fasting on triglyceride concentration tends to be more positive in many case studies. This may enhance health promotion for people who have no clinical conditions that may prevent them from fasting during the month of Ramadan. In a systematic review study, data revealed that 6 out of 15 studies reported reduction in triglyceride level at the end of Ramadan month. Nevertheless, other 9 studies showed no significant changes in triglycerides concentration [61]. Moreover, Ramadan fasting also has been found to be healthy by helping diabetic patients to reduce triglycerides level especially those who can fast the whole month of Ramadan. Recent evidence indicated clear effect of Ramadan fasting on triglycerides level in diabetic patients. Bener et al. [62] tried to investigate the effect of Ramadan fasting on some blood parameters including blood lipids (total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, etc.)

**117**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

fasting on HDL in different cases and population.

**13. The effect of Ramadan fasting on fasting plasma glucose**

Unhealthy elevation in fasting plasma glucose (FPG) has been found to be one of the MetS markers. The holy month of Ramadan has different lifestyle in most Muslim populations including diet and physical activity pattern which may influence the FPG [20]. Nevertheless, Ramadan fasting may help to reduce FPG even in diabetic individuals in both male and female [62]. However, the beneficial reduction in FPG during or end of Ramadan month seems to be temporary [67, 68]. Hence, any change in blood glucose during Ramadan is minor and improbable to affect healthy people especially if there is no major changes in diet or physical inactivity levels [69]. Recently, the effect of Ramadan fasting on FPG has been investigated in health young adults. The study found that Ramadan fasting elevated FPG significantly during the end of Ramadan comparing the levels before Ramadan. Nevertheless, the elevated value of FPG was within the normal level in both occasions [2]. On the other hand, Ramadan fasting may reduce FPG of apparently healthy young adults (19–23 years old) during the end of Ramadan month [70]. Furthermore, intermittent fasting such as Ramadan fasting improve FPG in obese/ overweight adults. One of the main outcomes of Ramadan fasting is losing weight and FPG as well as related metabolic parameters such as insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [71]. Insulin promotes the storage of glucose in liver and muscles as glycogen. However, during Ramadan fasting, circulating glucose levels decrease which lead to decrease the secretion of insulin and increase the level of glucagon hormone and catecholamines to enhance the

in patients with type 2 diabetes mellitus (T2DM) in Turkey. They concluded that fasting during the month of Ramadan may help to reduce triglycerides level even in people with type 2 diabetes [62]. Interestingly, rare of the available evidences showed negative effect of Ramadan fasting on triglycerides concentration. Thus, Ramadan fasting could enhance health promotion and reduce the risk of cardiovascular and metabolic diseases via the positive control of different lipid profile including triglyc-

**12. The effect of Ramadan fasting on high-density-lipoprotein (HDL)**

Health organizations recommend lifestyle that help to elevate high-densitylipoprotein (HDL) [46]. In general, a desired improvement has been found in plasma HDL at the end of Ramadan month and even after few weeks afterward [63]. Although there are some few studies that found no favorable changes in HDL as a result of Ramadan fasting [2, 64], recent strong evidences approved the health effect of Ramadan fasting on plasma HDL [61, 62]. However, the contradictory may due to the limitations of some studies. Kul et al. [65] did a meta-analysis to investigate the impact of Ramadan fasting on some health-related parameters in healthy population including blood lipids. They analyzed the data obtained from 13 studies to explore the effect of Ramadan fasting on HDL concentration (661 healthy individuals: 462 men and 199 women). They concluded that Ramadan fasting may help to reduce HDL concentration in women but not in men [65]. Moreover, the negative effect of Ramadan fasting has been observed in special population such as older adults with hypertension disease [66]. In sum, most of the recent and soled evidences have proved the beneficial effect of Ramadan fasting on plasma HDL level. Furthermore, more studies are encouraged to clarify the role of Ramadan

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

erides level.

*Blood Glucose Levels*

fasting has been found to reduce waist circumference even in apparently healthy young adults [54]. In some studies, the reported weight reduction occurred without significant changes in energy and macronutrient intake and physical activity level [4]. The reduction was interpreted as loss of body water and body fat percentage. There is a strong recent evidence that support the effect of Ramadan fasting on reducing body fat percentage and even fat-free mass especially with obese/ overweight people. In a recent review and meta-analysis study, data obtain from 70 publications found a significant reduction in fat percentage between pre-Ramadan and post-Ramadan in overweight and obesity individuals. (−1.46 [95% confidence interval: −2.57 to −0.35]%, *P* = 0.010). However, there was no changes reported in those of normal weight (−0.41 [−1.45 to 0.63]%, *P* = 0.436). The reduction also reported in fat-free mass between pre-Ramadan and post-Ramadan. Nevertheless, the changes in body composition measurements seem to be temporary. Evidences showed that body weight body composition parameters were returned toward the pre-Ramadan measurements just after 2–5 weeks from the month of Ramadan [37]. Furthermore, it has been suggested that this decrease in body weight could be attributed to a decrease in fluid intake [34, 55–57]. Sequentially, dehydration during the month of Ramadan may cause increase in urea and uric acid which is attributed to the reduction of the glomerular filtration rate [58]. The physiological aspects that may explain the association between Ramadan fasting and body composition parameters has been investigated. For instance, plasma leptin and insulin have been found to play a key role in body weight regulation homeostasis. Leptin level send signals to the brain about the amount of energy stores which in turn, stimulates the hypothalamic centers to regulate the energy intake and energy expenditure [59]. Although an evidence showed that there is a positive association between plasma leptin and insulin levels and body fat, the elevation in plasma leptin and insulin during the month of Ramadan is probably due to the energy intake and diet behavior [14]. In sum, Ramadan fasting may help to reduce body composition including central obesity such as waist circumference. However, the reduction may not be healthy as the weight loss attribute to loss of body water. One possible reason for this greater weight loss is that people with greater BMI are due to greater glycogen stores than people of normal weight, and hence would be expected to lose more fluid in response to fasting [60], and in some cases loss of lean tissue [34] carry more body. One of the most challenges is that body composition parameters are affected by different factors including calorie intake, physical activity level, age and gender. More investigations are needed to clarify the role of Ramadan fasting on

**116**

central obesity.

**11. The effect of Ramadan fasting on triglycerides**

In general, the role of Ramadan fasting on triglyceride concentration tends to be more positive in many case studies. This may enhance health promotion for people who have no clinical conditions that may prevent them from fasting during the month of Ramadan. In a systematic review study, data revealed that 6 out of 15 studies reported reduction in triglyceride level at the end of Ramadan month. Nevertheless, other 9 studies showed no significant changes in triglycerides concentration [61]. Moreover, Ramadan fasting also has been found to be healthy by helping diabetic patients to reduce triglycerides level especially those who can fast the whole month of Ramadan. Recent evidence indicated clear effect of Ramadan fasting on triglycerides level in diabetic patients. Bener et al. [62] tried to investigate the effect of Ramadan fasting on some blood parameters including blood lipids (total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, etc.)

in patients with type 2 diabetes mellitus (T2DM) in Turkey. They concluded that fasting during the month of Ramadan may help to reduce triglycerides level even in people with type 2 diabetes [62]. Interestingly, rare of the available evidences showed negative effect of Ramadan fasting on triglycerides concentration. Thus, Ramadan fasting could enhance health promotion and reduce the risk of cardiovascular and metabolic diseases via the positive control of different lipid profile including triglycerides level.

### **12. The effect of Ramadan fasting on high-density-lipoprotein (HDL)**

Health organizations recommend lifestyle that help to elevate high-densitylipoprotein (HDL) [46]. In general, a desired improvement has been found in plasma HDL at the end of Ramadan month and even after few weeks afterward [63]. Although there are some few studies that found no favorable changes in HDL as a result of Ramadan fasting [2, 64], recent strong evidences approved the health effect of Ramadan fasting on plasma HDL [61, 62]. However, the contradictory may due to the limitations of some studies. Kul et al. [65] did a meta-analysis to investigate the impact of Ramadan fasting on some health-related parameters in healthy population including blood lipids. They analyzed the data obtained from 13 studies to explore the effect of Ramadan fasting on HDL concentration (661 healthy individuals: 462 men and 199 women). They concluded that Ramadan fasting may help to reduce HDL concentration in women but not in men [65]. Moreover, the negative effect of Ramadan fasting has been observed in special population such as older adults with hypertension disease [66]. In sum, most of the recent and soled evidences have proved the beneficial effect of Ramadan fasting on plasma HDL level. Furthermore, more studies are encouraged to clarify the role of Ramadan fasting on HDL in different cases and population.

#### **13. The effect of Ramadan fasting on fasting plasma glucose**

Unhealthy elevation in fasting plasma glucose (FPG) has been found to be one of the MetS markers. The holy month of Ramadan has different lifestyle in most Muslim populations including diet and physical activity pattern which may influence the FPG [20]. Nevertheless, Ramadan fasting may help to reduce FPG even in diabetic individuals in both male and female [62]. However, the beneficial reduction in FPG during or end of Ramadan month seems to be temporary [67, 68]. Hence, any change in blood glucose during Ramadan is minor and improbable to affect healthy people especially if there is no major changes in diet or physical inactivity levels [69]. Recently, the effect of Ramadan fasting on FPG has been investigated in health young adults. The study found that Ramadan fasting elevated FPG significantly during the end of Ramadan comparing the levels before Ramadan. Nevertheless, the elevated value of FPG was within the normal level in both occasions [2]. On the other hand, Ramadan fasting may reduce FPG of apparently healthy young adults (19–23 years old) during the end of Ramadan month [70]. Furthermore, intermittent fasting such as Ramadan fasting improve FPG in obese/ overweight adults. One of the main outcomes of Ramadan fasting is losing weight and FPG as well as related metabolic parameters such as insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [71]. Insulin promotes the storage of glucose in liver and muscles as glycogen. However, during Ramadan fasting, circulating glucose levels decrease which lead to decrease the secretion of insulin and increase the level of glucagon hormone and catecholamines to enhance the

breakdown of glycogen to provide body with energy [64]. Hence, one can conclude that Ramadan fasting may improve FPG especially after a couple of weeks. One of the explanation is that alterations in lifestyle during the month of Ramadan may lead to changes in the rhythmic pattern of different related hormonal including thyroid hormones, melatonin, pituitary hormones (prolactin, luteinizing hormone, follicular stimulating hormone, growth hormone and thyroid-stimulating hormone) and steroid hormones (cortisol and testosterone) [72]. These hormones are related to energy metabolism and regulation of energy intake [14, 72]. These hormonal changes could explain decreases in blood glucose levels.

However, FPG may return to previous level afterward. Thus, intermittent fasting is recommended to reduce the risk of having one or more of the MetS markers such as FPG.

#### **14. The effect of Ramadan fasting on blood pressure**

Blood pressure (BP) is one of the complicated factors liked to different cardiovascular diseases.

High blood pressure is one of the MetS that may develop cardiovascular and metabolic diseases [52]. Although some studies reported slight, but significant, elevation in blood pressure in apparently healthy young adults during the month of Ramadan [2], different evidences concluded that Ramadan fasting may lead to reduce blood pressure in apparently healthy people as well as patients with hypertension, stable cardiovascular, metabolic syndrome and dyslipidemia [73]. In a systematical review study, Mazidi and colleagues found that data from different studies reported reduction in blood pressure especially systolic blood pressure (SBP) but no significant changes has been observed in diastolic blood pressure (DBP) [61]. Data from several investigations revealed that Ramadan fasting could reduce blood pressure unless there are some conditions that may influence BP such as diet and stress [74–76]. However, Topacoglu et al. [77] observed an increase in the number of admissions for hypertension during the holy month of Ramadan [77]. The reduction in blood pressure parameters during the month of Ramadan can be explained as a result of dehydration due to the long fasting time. On the other hand, it can be attributed to lower daytime activity which may cause a noticeable reduction in sympathetic tone [78]. In some countries the holy month of Ramadan comes in hot season (June–August) which makes people fast longer (~15 hours). Therefore, hypertensive patient should be advised to avoid diuretics during fasting and they can fast with paying attention to type and amount of food that may raise BP [79]. Remarkably, very few available evidences observed unhealthy effects of Ramadan fasting on hypertensive patients. In fact, the role of Ramadan fasting on controlling blood pressure is controversial. Partly, it is due to the lack of the available evidences that investigated the comprehensive effect of Ramadan fasting on blood pressure in people with different health conditions. Thus, more investigations are recommended to clarify the role of Ramadan fasting on blood pressure parameters.

#### **15. Conclusion**

The effect of Ramadan fasting on most of the MetS markers is still controversial. However, most of the available evidences showed positive effect on most of the MetS markers. In general, Ramadan fasting may help to reduce the risk of MetS. Nevertheless, most of the positive results seem to be impermanent and

**119**

**Author details**

Khalid S. Aljaloud

King Saud University, Riyadh, Saudi Arabia

provided the original work is properly cited.

\*Address all correspondence to: khaljaloud@ksu.edu.sa

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

reading of many of the variables (MetS markers) return to the previous reading after few weeks (~3–4 weeks). Therefore, intermittent fasting such as Ramadan fasting could be one of the cure alternatives especially in people with MetS, cardiovascular or metabolic diseases with considering their physician supervision. In general, Ramadan fasting is associated with positive improvements in different related hormones such as insulin, leptin, adiponectin, adipocytokine, Gamma glutamyl transferase and others that may be directly or indirectly affect MetS markers. Hence, Ramadan as an intermittent fasting might be more beneficial for most population and cardiovascular and metabolic patients should consult their physicians when they decide to fast during the month of Ramadan. Again, more evidences are recommended to clarify the controversial issues related to the role of

Department of Exercise Physiology, College of Sport Sciences and Physical Activity,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

Ramadan fasting on MetS markers.

#### *The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

*Blood Glucose Levels*

such as FPG.

vascular diseases.

breakdown of glycogen to provide body with energy [64]. Hence, one can conclude that Ramadan fasting may improve FPG especially after a couple of weeks. One of the explanation is that alterations in lifestyle during the month of Ramadan may lead to changes in the rhythmic pattern of different related hormonal including thyroid hormones, melatonin, pituitary hormones (prolactin, luteinizing hormone, follicular stimulating hormone, growth hormone and thyroid-stimulating hormone) and steroid hormones (cortisol and testosterone) [72]. These hormones are related to energy metabolism and regulation of energy intake [14, 72]. These

However, FPG may return to previous level afterward. Thus, intermittent fasting is recommended to reduce the risk of having one or more of the MetS markers

Blood pressure (BP) is one of the complicated factors liked to different cardio-

High blood pressure is one of the MetS that may develop cardiovascular and metabolic diseases [52]. Although some studies reported slight, but significant, elevation in blood pressure in apparently healthy young adults during the month of Ramadan [2], different evidences concluded that Ramadan fasting may lead to reduce blood pressure in apparently healthy people as well as patients with hypertension, stable cardiovascular, metabolic syndrome and dyslipidemia [73]. In a systematical review study, Mazidi and colleagues found that data from different studies reported reduction in blood pressure especially systolic blood pressure (SBP) but no significant changes has been observed in diastolic blood pressure (DBP) [61]. Data from several investigations revealed that Ramadan fasting could reduce blood pressure unless there are some conditions that may influence BP such as diet and stress [74–76]. However, Topacoglu et al. [77] observed an increase in the number of admissions for hypertension during the holy month of Ramadan [77]. The reduction in blood pressure parameters during the month of Ramadan can be explained as a result of dehydration due to the long fasting time. On the other hand, it can be attributed to lower daytime activity which may cause a noticeable reduction in sympathetic tone [78]. In some countries the holy month of Ramadan comes in hot season (June–August) which makes people fast longer (~15 hours). Therefore, hypertensive patient should be advised to avoid diuretics during fasting and they can fast with paying attention to type and amount of food that may raise BP [79]. Remarkably, very few available evidences observed unhealthy effects of Ramadan fasting on hypertensive patients. In fact, the role of Ramadan fasting on controlling blood pressure is controversial. Partly, it is due to the lack of the available evidences that investigated the comprehensive effect of Ramadan fasting on blood pressure in people with different health conditions. Thus, more investigations are recommended to clarify the role of Ramadan fasting on blood pressure

The effect of Ramadan fasting on most of the MetS markers is still controversial. However, most of the available evidences showed positive effect on most of the MetS markers. In general, Ramadan fasting may help to reduce the risk of MetS. Nevertheless, most of the positive results seem to be impermanent and

hormonal changes could explain decreases in blood glucose levels.

**14. The effect of Ramadan fasting on blood pressure**

**118**

parameters.

**15. Conclusion**

reading of many of the variables (MetS markers) return to the previous reading after few weeks (~3–4 weeks). Therefore, intermittent fasting such as Ramadan fasting could be one of the cure alternatives especially in people with MetS, cardiovascular or metabolic diseases with considering their physician supervision. In general, Ramadan fasting is associated with positive improvements in different related hormones such as insulin, leptin, adiponectin, adipocytokine, Gamma glutamyl transferase and others that may be directly or indirectly affect MetS markers. Hence, Ramadan as an intermittent fasting might be more beneficial for most population and cardiovascular and metabolic patients should consult their physicians when they decide to fast during the month of Ramadan. Again, more evidences are recommended to clarify the controversial issues related to the role of Ramadan fasting on MetS markers.

### **Author details**

Khalid S. Aljaloud

Department of Exercise Physiology, College of Sport Sciences and Physical Activity, King Saud University, Riyadh, Saudi Arabia

\*Address all correspondence to: khaljaloud@ksu.edu.sa

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Ranasinghe P, Mathangasinghe Y, Jayawardena R, Hills A, Misra A. Prevalence and trends of metabolic syndrome among adults in the asiapacific region: A systematic review. BMC Public Health. 2017;**17**(1):101

[2] Al-barha NS, Aljaloud KS. The effect of Ramadan fasting on body composition and metabolic syndrome in apparently healthy men. American Journal of Men's Health. 2019;**13**(1):1557988318816925

[3] Alkandari JR, Maughan RJ, Roky R, Aziz AR, Karli U. The implications of Ramadan fasting for human health and well-being. Journal of Sports Sciences. 2012;**30**(suppl1):S9-S19

[4] Al-Hourani H, Atoum M. Body composition, nutrient intake and physical activity patterns in young women during Ramadan. Singapore Medical Journal. 2007;**48**(10):906

[5] Al-Numair K. Body weight and some biochemical changes associated with Ramadan fasting in healthy Saudi men. Journal of Medical Sciences. 2006;**6**(1):112-116

[6] el Ati J, Beji C, Danguir J. Increased fat oxidation during Ramadan fasting in healthy women: An adaptative mechanism for body-weight maintenance. The American Journal of Clinical Nutrition. 1995;**62**(2):302-307. DOI: 10.1093/ajcn/62.2.302

[7] Fakhrzadeh H, Larijani B, Sanjari M, Baradar-Jalili R, Amini MR. Effect of Ramadan fasting on clinical and biochemical parameters in healthy adults. Annals of Saudi Medicine. 2003;**23**(3-4):223-226. DOI: 10.5144/0256-4947.2003.223

[8] Faris MA, Kacimi S, Al-Kurd RA, Fararjeh MA, Bustanji YK, Mohammad MK, et al. Intermittent

fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutrition Research. 2012;**32**(12):947-955. DOI: 10.1016/j.nutres.2012.06.021

[9] Haouari-Oukerro F, Ben-Attia M, Kaâbachi N, Haouari M. Ramadan fasting influences on food intake consumption, sleep schedule, body weight and some plasma parameters in healthy fasting volunteers. African Journal of Biotechnology. 2013;**12**(21):3327-3332

[10] Haouari M, Haouari-Oukerro F, Sfaxi A, Rayana MB, Kaabachi N, Mbazaa A. How Ramadan fasting affects caloric consumption, body weight, and circadian evolution of cortisol serum levels in young, healthy male volunteers. Hormone and Metabolic Research. 2008;**40**(08):575-577

[11] Ibrahim WH, Habib HM, Jarrar AH, Al Baz SA. Effect of Ramadan fasting on markers of oxidative stress and serum biochemical markers of cellular damage in healthy subjects. Annals of Nutrition and Metabolism. 2008;**53**(3-4):175-181. DOI: 10.1159/000172979

[12] Trabelsi K, El Abed K, Trepanowski JF, Stannard SR, Ghlissi Z, Ghozzi H, et al. Effects of ramadan fasting on biochemical and anthropometric parameters in physically active men. Asian Journal of Sports Medicine. 2011;**2**(3):134-144

[13] Adlouni A, Ghalim N, Saile R, Hda N, Parra HJ, Benslimane A. Beneficial effect on serum apo AI, apo B and Lp AI levels of Ramadan fasting. Clinica Chimica Acta. 1998;**271**(2):179-189. DOI: 10.1016/ s0009-8981(97)00245-3

[14] Kassab S, Abdul-Ghaffar T, Nagalla DS, Sachdeva U, Nayar U. Interactions between leptin,

**121**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

americansphysical activity guidelines for AmericansPhysical Activity Guidelines for Americans. JAMA. 2018;**320**(19):2020-2028. DOI: 10.1001/

[22] Ramadan JM, Barac-Nieto M. Cardio-respiratory responses to moderately heavy aerobic exercise during the Ramadan fasts. Saudi Medical Journal. 2000;**21**(3):238-244

[23] Roky R, Houti I, Moussamih S, Qotbi S, Aadil N. Physiological and chronobiological changes during Ramadan intermittent fasting. Annals of Nutrition and Metabolism.

[24] Afifi ZEM. Daily practices, study performance and health during the Ramadan fast. Journal of the Royal Society of Health. 1997;**117**(4):231-235. DOI: 10.1177/146642409711700406

[25] BaHammam A. Sleep pattern, daytime sleepiness, and eating habits during the month of Ramadan. Sleep

[26] Soh K, Soh K, Ong S, Aminuddin Y, Ruby H. Comparing physical activity of Malaysian Malay men before, during, and after Ramadan: Physical activity and health. African Journal for Physical Health Education, Recreation and

and Hypnosis. 2003;**5**:165-174

Dance. 2010;**16**(1):74-81

2010;**16**(3):343-349

[27] Soh K, Soh K, Ruby H,

Salimah J. Physical activity of female Malay Muslims before, during and after Ramadan: Physical activity. African Journal for Physical Health Education, Recreation and Dance.

[28] Wilson NC. Pedometer-assessed physical activity of urban Malaysian youth. ISN Bulletin. 2009;**2**:9-18

[29] Bakhotmah BA. The puzzle of self-reported weight gain in a month of

2004;**48**(4):296-303. DOI:

10.1159/000081076

jama.2018.14854

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

neuropeptide-Y and insulin with chronic diurnal fasting during Ramadan. Annals of Saudi Medicine. 2004;**24**(5):345-349. DOI: 10.5144/0256-4947.2004.345

[16] Sweileh N, Schnitzler A, Hunter GR, Davis B. Body composition and energy metabolism in resting and exercising muslims during Ramadan fast. The Journal of Sports Medicine and Physical

[17] Gibson AA, Hsu MS, Rangan AM, Seimon RV, Lee CM, Das A, et al. Accuracy of hands v. household measures as portion size estimation aids. Journal of Nutritional Science. 2016;**5**:e29. DOI: 10.1017/jns.2016.22

[18] Livingstone M, Prentice A, Strain J, Coward W, Black A, Barker M, et al. Accuracy of weighed dietary records in studies of diet and health. BMJ.

[19] Khaled BM, Belbraouet S. Effect of Ramadan fasting on anthropometric parameters and food consumption in 276 type 2 diabetic obese women. International Journal of Diabetes in Developing Countries. 2009;**29**(2):62

[20] Sadiya A, Ahmed S, Siddieg HH, Babas IJ, Carlsson M. Effect of Ramadan fasting on metabolic markers, body composition, and dietary intake in Emiratis of Ajman (UAE) with metabolic syndrome. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2011;**4**:409

[21] Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The physical activity guidelines for

Fitness. 1992;**32**(2):156-163

1990;**300**(6726):708-712

[15] Lamri-Senhadji M, El Kebir B, Belleville J, Bouchenak M. Assessment of dietary consumption and timecourse of changes in serum lipids and lipoproteins before, during and after Ramadan in young Algerian adults. Singapore Medical Journal.

2009;**50**(3):288

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

neuropeptide-Y and insulin with chronic diurnal fasting during Ramadan. Annals of Saudi Medicine. 2004;**24**(5):345-349. DOI: 10.5144/0256-4947.2004.345

[15] Lamri-Senhadji M, El Kebir B, Belleville J, Bouchenak M. Assessment of dietary consumption and timecourse of changes in serum lipids and lipoproteins before, during and after Ramadan in young Algerian adults. Singapore Medical Journal. 2009;**50**(3):288

[16] Sweileh N, Schnitzler A, Hunter GR, Davis B. Body composition and energy metabolism in resting and exercising muslims during Ramadan fast. The Journal of Sports Medicine and Physical Fitness. 1992;**32**(2):156-163

[17] Gibson AA, Hsu MS, Rangan AM, Seimon RV, Lee CM, Das A, et al. Accuracy of hands v. household measures as portion size estimation aids. Journal of Nutritional Science. 2016;**5**:e29. DOI: 10.1017/jns.2016.22

[18] Livingstone M, Prentice A, Strain J, Coward W, Black A, Barker M, et al. Accuracy of weighed dietary records in studies of diet and health. BMJ. 1990;**300**(6726):708-712

[19] Khaled BM, Belbraouet S. Effect of Ramadan fasting on anthropometric parameters and food consumption in 276 type 2 diabetic obese women. International Journal of Diabetes in Developing Countries. 2009;**29**(2):62

[20] Sadiya A, Ahmed S, Siddieg HH, Babas IJ, Carlsson M. Effect of Ramadan fasting on metabolic markers, body composition, and dietary intake in Emiratis of Ajman (UAE) with metabolic syndrome. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2011;**4**:409

[21] Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The physical activity guidelines for americansphysical activity guidelines for AmericansPhysical Activity Guidelines for Americans. JAMA. 2018;**320**(19):2020-2028. DOI: 10.1001/ jama.2018.14854

[22] Ramadan JM, Barac-Nieto M. Cardio-respiratory responses to moderately heavy aerobic exercise during the Ramadan fasts. Saudi Medical Journal. 2000;**21**(3):238-244

[23] Roky R, Houti I, Moussamih S, Qotbi S, Aadil N. Physiological and chronobiological changes during Ramadan intermittent fasting. Annals of Nutrition and Metabolism. 2004;**48**(4):296-303. DOI: 10.1159/000081076

[24] Afifi ZEM. Daily practices, study performance and health during the Ramadan fast. Journal of the Royal Society of Health. 1997;**117**(4):231-235. DOI: 10.1177/146642409711700406

[25] BaHammam A. Sleep pattern, daytime sleepiness, and eating habits during the month of Ramadan. Sleep and Hypnosis. 2003;**5**:165-174

[26] Soh K, Soh K, Ong S, Aminuddin Y, Ruby H. Comparing physical activity of Malaysian Malay men before, during, and after Ramadan: Physical activity and health. African Journal for Physical Health Education, Recreation and Dance. 2010;**16**(1):74-81

[27] Soh K, Soh K, Ruby H, Salimah J. Physical activity of female Malay Muslims before, during and after Ramadan: Physical activity. African Journal for Physical Health Education, Recreation and Dance. 2010;**16**(3):343-349

[28] Wilson NC. Pedometer-assessed physical activity of urban Malaysian youth. ISN Bulletin. 2009;**2**:9-18

[29] Bakhotmah BA. The puzzle of self-reported weight gain in a month of

**120**

*Blood Glucose Levels*

**References**

[1] Ranasinghe P, Mathangasinghe Y, Jayawardena R, Hills A, Misra A. Prevalence and trends of metabolic syndrome among adults in the asiapacific region: A systematic review. BMC Public Health. 2017;**17**(1):101

fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutrition Research. 2012;**32**(12):947-955. DOI: 10.1016/j.nutres.2012.06.021

[9] Haouari-Oukerro F, Ben-Attia M, Kaâbachi N, Haouari M. Ramadan fasting influences on food intake consumption, sleep schedule, body weight and some plasma parameters in healthy fasting volunteers. African Journal of Biotechnology.

[10] Haouari M, Haouari-Oukerro F, Sfaxi A, Rayana MB, Kaabachi N, Mbazaa A. How Ramadan fasting affects caloric consumption, body weight, and circadian evolution of cortisol serum levels in young, healthy male volunteers. Hormone and Metabolic Research.

[11] Ibrahim WH, Habib HM, Jarrar AH, Al Baz SA. Effect of Ramadan fasting on markers of oxidative stress and serum biochemical markers of cellular damage in healthy subjects. Annals of Nutrition and Metabolism. 2008;**53**(3-4):175-181.

Trepanowski JF, Stannard SR, Ghlissi Z, Ghozzi H, et al. Effects of ramadan

anthropometric parameters in physically active men. Asian Journal of Sports Medicine. 2011;**2**(3):134-144

[13] Adlouni A, Ghalim N, Saile R, Hda N, Parra HJ, Benslimane A. Beneficial effect on serum apo AI, apo B and Lp AI levels of Ramadan fasting. Clinica Chimica Acta. 1998;**271**(2):179-189. DOI: 10.1016/

2013;**12**(21):3327-3332

2008;**40**(08):575-577

DOI: 10.1159/000172979

[12] Trabelsi K, El Abed K,

fasting on biochemical and

s0009-8981(97)00245-3

[14] Kassab S, Abdul-Ghaffar T, Nagalla DS, Sachdeva U, Nayar U. Interactions between leptin,

[2] Al-barha NS, Aljaloud KS. The effect of Ramadan fasting on body composition and metabolic syndrome

American Journal of Men's Health. 2019;**13**(1):1557988318816925

[4] Al-Hourani H, Atoum M. Body composition, nutrient intake and physical activity patterns in young women during Ramadan. Singapore Medical Journal. 2007;**48**(10):906

[5] Al-Numair K. Body weight and some biochemical changes associated with Ramadan fasting in healthy Saudi men. Journal of Medical Sciences.

[6] el Ati J, Beji C, Danguir J. Increased fat oxidation during Ramadan fasting in healthy women: An adaptative mechanism for body-weight

maintenance. The American Journal of Clinical Nutrition. 1995;**62**(2):302-307.

[7] Fakhrzadeh H, Larijani B, Sanjari M, Baradar-Jalili R, Amini MR. Effect of Ramadan fasting on clinical and biochemical parameters in healthy adults. Annals of Saudi Medicine. 2003;**23**(3-4):223-226. DOI: 10.5144/0256-4947.2003.223

[8] Faris MA, Kacimi S, Al-Kurd RA,

Mohammad MK, et al. Intermittent

Fararjeh MA, Bustanji YK,

DOI: 10.1093/ajcn/62.2.302

[3] Alkandari JR, Maughan RJ, Roky R, Aziz AR, Karli U. The implications of Ramadan fasting for human health and well-being. Journal of Sports Sciences.

in apparently healthy men.

2012;**30**(suppl1):S9-S19

2006;**6**(1):112-116

fasting (Ramadan) among a cohort of Saudi families in Jeddah, Western Saudi Arabia. Nutrition Journal. 2011;**10**(1):84

[30] Lessan N, Saadane I, Alkaf B, Hambly C, Buckley AJ, Finer N, et al. The effects of Ramadan fasting on activity and energy expenditure. The American Journal of Clinical Nutrition. 2018;**107**(1):54-61

[31] Meckel Y, Ismaeel A, Eliakim A. The effect of the Ramadan fast on physical performance and dietary habits in adolescent soccer players. European Journal of Applied Physiology. 2008;**102**(6):651-657. DOI: 10.1007/ s00421-007-0633-2

[32] Ford ES, Kohl HW III, Mokdad AH, Ajani UA. Sedentary behavior, physical activity, and the metabolic syndrome among US adults. Obesity Research. 2005;**13**(3):608-614

[33] Asl NS. The effects of Ramadan fasting on endurance running performance in male athletes. International Journal of Sport Studies. 2011;**1**:18-22

[34] Leiper J, Molla A. Effects on health of fluid restriction during fasting in Ramadan. European Journal of Clinical Nutrition. 2003;**57**:S30-S38

[35] Ongsara S, Boonpol S, Prompalad N, Jeenduang N. The effect of Ramadan fasting on biochemical parameters in healthy Thai subjects. Journal of Clinical and Diagnostic Research—JCDR. 2017;**11**(9):BC14

[36] Sadeghirad B, Motaghipisheh S, Kolahdooz F, Zahedi MJ, Haghdoost AA. Islamic fasting and weight loss: A systematic review and meta-analysis. Public Health Nutrition. 2012;**27**:1-11

[37] Fernando HA, Zibellini J, Harris RA, Seimon RV, Sainsbury A. Effect of Ramadan fasting on weight and body

composition in healthy non-athlete adults: A systematic review and metaanalysis. Nutrients. 2019;**11**(2):478

[38] Bahammam A. Does Ramadan fasting affect sleep? International Journal of Clinical Practice. 2006;**60**(12):1631-1637

[39] Mansi KMS. Study the effects of Ramadan fasting on the serum glucose and lipid profile among healthy Jordanian students. American Journal of Applied Sciences. 2007;**4**(8):565-569

[40] Ramadan J. Does fasting during Ramadan alter body composition, blood constituents and physical performance? Medical Principles and Practice. 2002;**11**(Suppl. 2):41-46

[41] Qasrawi SO, Pandi-Perumal SR, BaHammam AS. The effect of intermittent fasting during Ramadan on sleep, sleepiness, cognitive function, and circadian rhythm. Sleep and Breathing. 2017;**21**(3):577-586. DOI: 10.1007/s11325-017-1473-x

[42] Kylin E. Studien ueber das Hypertonie-Hyperglyka "mie-Hyperurika" miesyndrom. Zentralblatt für innere Medizin. 1923;**44**:105-127

[43] Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community cohort with schizophrenia. The British Journal of Psychiatry. 2010;**196**(2):116-121. DOI: 10.1192/bjp.bp.109.067512

[44] Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: Is the differential mortality gap worsening over time? Archives of General Psychiatry. 2007;**64**(10):1123-1131. DOI: 10.1001/ archpsyc.64.10.1123

[45] Despres J. Abdominal obesity as important component of insulinresistance syndrome. Nutrition

**123**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

[53] Kyle U, Genton L, Hans D, Karsegard L, Slosman D, Pichard C. Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. European Journal of Clinical Nutrition.

[54] Saleh SA, Elsharouni SA, Cherian B, Mourou M. Effects of Ramadan fasting on waist circumference, blood pressure, lipid profile, and blood sugar on a sample of healthy Kuwaiti men and women. Malaysian Journal of Nutrition.

[55] Husain R, Duncan M, Cheah S, Ch'Ng S. Effects of fasting in Ramadan on tropical Asiatic Moslems. British Journal of Nutrition. 1987;**58**(1):41-48

[56] Rahman M, Rashid M, Basher S, Sultana S, Nomani M. 2004. Improved

[57] Ziaee V, Razaei M, Ahmadinejad Z, Shaikh H, Yousefi R, Yarmohammadi L,

serum HDL cholesterol profile among Bangladeshi male students during Ramadan fasting. Eastern Mediterranean Health Journal.

et al. The changes of metabolic profile and weight during Ramadan fasting. Singapore Medical Journal.

[58] Argani H, Mozaffari S,

Rahnama B, Rahbani M, Rejaie M, Ghafari A. Evaluation of biochemical and immunologic changes in renal transplant recipients during Ramadan

fasting. Paper presented at the Transplantation proceedings. 2003

[59] Havel PJ. Leptin production and action: Relevance to energy balance in humans. The American Journal of Clinical Nutrition. 1998;**67**:355-356

[60] Verdich C, Barbe P, Petersen M, Grau K, Ward L, Macdonald I, et al. Changes in body composition during

2001;**55**(8):663

2005;**11**(2):143-150

2004;**10**(1):131-137

2006;**47**(5):409

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

(Burbank, Los Angeles County, California). 1993;**9**(5):452-459

[46] Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification

[47] Expert Panel on Detection.

Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA.

[48] Kahn R. Follow-up report on the diagnosis of diabetes mellitus: The expert committee on the diagnosis and classifications of diabetes mellitus. Diabetes Care. 2003;**26**(11):3160

[49] Shaw JE, Zimmet PZ, Alberti KGM. Point: Impaired fasting glucose: The case for the new American Diabetes Association criterion. Diabetes Care.

complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine.

of diabetes mellitus and its

1998;**15**(7):539-553

2001;**285**(19):2486

2006;**29**(5):1170-1172

2015;**10**(5):e0126832

Dabelea D, Hernandez TL,

Reviews. 2008;**29**(7):777-822

[52] Zafar U, Khaliq S, Ahmad HU, Manzoor S, Lone KP. Metabolic syndrome:

An update on diagnostic criteria, pathogenesis, and genetic links. Hormones. 2018;**17**(3):299-313

Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocrine

[51] Cornier M-A,

[50] Wen J, Yang J, Shi Y, Liang Y, Wang F, Duan X, et al. Comparisons of different metabolic syndrome definitions and associations with coronary heart disease, stroke, and peripheral arterial disease in a rural Chinese population. PLoS One.

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

(Burbank, Los Angeles County, California). 1993;**9**(5):452-459

*Blood Glucose Levels*

2018;**107**(1):54-61

s00421-007-0633-2

2005;**13**(3):608-614

2011;**1**:18-22

2017;**11**(9):BC14

2012;**27**:1-11

Kolahdooz F, Zahedi MJ,

fasting (Ramadan) among a cohort of Saudi families in Jeddah, Western Saudi Arabia. Nutrition Journal. 2011;**10**(1):84 composition in healthy non-athlete adults: A systematic review and metaanalysis. Nutrients. 2019;**11**(2):478

[38] Bahammam A. Does Ramadan fasting affect sleep? International Journal of Clinical Practice. 2006;**60**(12):1631-1637

[39] Mansi KMS. Study the effects of Ramadan fasting on the serum glucose and lipid profile among healthy Jordanian students. American

[40] Ramadan J. Does fasting during Ramadan alter body composition, blood constituents and physical performance?

[41] Qasrawi SO, Pandi-Perumal SR, BaHammam AS. The effect of intermittent fasting during Ramadan on sleep, sleepiness, cognitive function, and circadian rhythm. Sleep and Breathing. 2017;**21**(3):577-586. DOI: 10.1007/s11325-017-1473-x

Medical Principles and Practice.

[42] Kylin E. Studien ueber das Hypertonie-Hyperglyka "mie-

[43] Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality

schizophrenia. The British Journal of Psychiatry. 2010;**196**(2):116-121. DOI: 10.1192/bjp.bp.109.067512

[44] Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: Is the differential mortality gap worsening over time? Archives of General Psychiatry. 2007;**64**(10):1123-1131. DOI: 10.1001/

[45] Despres J. Abdominal obesity as important component of insulinresistance syndrome. Nutrition

of a community cohort with

archpsyc.64.10.1123

Hyperurika" miesyndrom. Zentralblatt für innere Medizin. 1923;**44**:105-127

2002;**11**(Suppl. 2):41-46

Journal of Applied Sciences.

2007;**4**(8):565-569

[30] Lessan N, Saadane I, Alkaf B, Hambly C, Buckley AJ, Finer N, et al. The effects of Ramadan fasting on activity and energy expenditure. The American Journal of Clinical Nutrition.

[31] Meckel Y, Ismaeel A, Eliakim A. The effect of the Ramadan fast on physical performance and dietary habits in adolescent soccer players. European Journal of Applied Physiology. 2008;**102**(6):651-657. DOI: 10.1007/

[32] Ford ES, Kohl HW III, Mokdad AH, Ajani UA. Sedentary behavior, physical activity, and the metabolic syndrome among US adults. Obesity Research.

[33] Asl NS. The effects of Ramadan fasting on endurance running performance in male athletes.

International Journal of Sport Studies.

[34] Leiper J, Molla A. Effects on health of fluid restriction during fasting in Ramadan. European Journal of Clinical

[35] Ongsara S, Boonpol S, Prompalad N, Jeenduang N. The effect of Ramadan fasting on biochemical parameters in healthy Thai subjects. Journal of Clinical and Diagnostic Research—JCDR.

[36] Sadeghirad B, Motaghipisheh S,

Haghdoost AA. Islamic fasting and weight loss: A systematic review and meta-analysis. Public Health Nutrition.

[37] Fernando HA, Zibellini J, Harris RA, Seimon RV, Sainsbury A. Effect of Ramadan fasting on weight and body

Nutrition. 2003;**57**:S30-S38

**122**

[46] Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine. 1998;**15**(7):539-553

[47] Expert Panel on Detection. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;**285**(19):2486

[48] Kahn R. Follow-up report on the diagnosis of diabetes mellitus: The expert committee on the diagnosis and classifications of diabetes mellitus. Diabetes Care. 2003;**26**(11):3160

[49] Shaw JE, Zimmet PZ, Alberti KGM. Point: Impaired fasting glucose: The case for the new American Diabetes Association criterion. Diabetes Care. 2006;**29**(5):1170-1172

[50] Wen J, Yang J, Shi Y, Liang Y, Wang F, Duan X, et al. Comparisons of different metabolic syndrome definitions and associations with coronary heart disease, stroke, and peripheral arterial disease in a rural Chinese population. PLoS One. 2015;**10**(5):e0126832

[51] Cornier M-A, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocrine Reviews. 2008;**29**(7):777-822

[52] Zafar U, Khaliq S, Ahmad HU, Manzoor S, Lone KP. Metabolic syndrome: An update on diagnostic criteria, pathogenesis, and genetic links. Hormones. 2018;**17**(3):299-313

[53] Kyle U, Genton L, Hans D, Karsegard L, Slosman D, Pichard C. Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. European Journal of Clinical Nutrition. 2001;**55**(8):663

[54] Saleh SA, Elsharouni SA, Cherian B, Mourou M. Effects of Ramadan fasting on waist circumference, blood pressure, lipid profile, and blood sugar on a sample of healthy Kuwaiti men and women. Malaysian Journal of Nutrition. 2005;**11**(2):143-150

[55] Husain R, Duncan M, Cheah S, Ch'Ng S. Effects of fasting in Ramadan on tropical Asiatic Moslems. British Journal of Nutrition. 1987;**58**(1):41-48

[56] Rahman M, Rashid M, Basher S, Sultana S, Nomani M. 2004. Improved serum HDL cholesterol profile among Bangladeshi male students during Ramadan fasting. Eastern Mediterranean Health Journal. 2004;**10**(1):131-137

[57] Ziaee V, Razaei M, Ahmadinejad Z, Shaikh H, Yousefi R, Yarmohammadi L, et al. The changes of metabolic profile and weight during Ramadan fasting. Singapore Medical Journal. 2006;**47**(5):409

[58] Argani H, Mozaffari S, Rahnama B, Rahbani M, Rejaie M, Ghafari A. Evaluation of biochemical and immunologic changes in renal transplant recipients during Ramadan fasting. Paper presented at the Transplantation proceedings. 2003

[59] Havel PJ. Leptin production and action: Relevance to energy balance in humans. The American Journal of Clinical Nutrition. 1998;**67**:355-356

[60] Verdich C, Barbe P, Petersen M, Grau K, Ward L, Macdonald I, et al. Changes in body composition during weight loss in obese subjects in the NUGENOB study: Comparison of bioelectrical impedance vs. dual-energy X-ray absorptiometry. Diabetes and Metabolism. 2011;**37**(3):222-229. DOI: 10.1016/j.diabet.2010.10.007

[61] Mazidi M, Rezaie P, Chaudhri O, Karimi E, Nematy M. The effect of Ramadan fasting on cardiometabolic risk factors and anthropometrics parameters: A systematic review. Pakistan Journal of Medical Sciences. 2015;**31**(5):1250

[62] Bener A, Al-Hamaq AO, Öztürk M, Çatan F, Haris PI, Rajput KU, et al. Effect of ramadan fasting on glycemic control and other essential variables in diabetic patients. Annals of African Medicine. 2018;**17**(4):196

[63] Shehab A, Abdulle A, El Issa A, Al Suwaidi J, Nagelkerke N. Favorable changes in lipid profile: The effects of fasting after Ramadan. PLoS One. 2012;**7**(10):e47615

[64] Maislos M, Khamaysi N, Assali A, Abou-Rabiah Y, Zvili I, Shany S. Marked increase in plasma high-densitylipoprotein cholesterol after prolonged fasting during Ramadan. The American Journal of Clinical Nutrition. 1993;**57**(5):640-642. DOI: 10.1093/ ajcn/57.5.640

[65] Kul S, Savaş E, Öztürk ZA, Karadağ G. Does Ramadan fasting alter body weight and blood lipids and fasting blood glucose in a healthy population? A meta-analysis. Journal of Religion and Health. 2014;**53**(3):929-942

[66] Akturk I, Biyik I, Kocas C, Yalcin A, Erturk M, Uzun F. PP-106 Effects of Ramadan fasting on lipid profile, brain nadriuretic peptide, renal functions and electrolyte levels in patients with hypertension. International Journal of Cardiology. 2012;**155**:S134

[67] Rouhani MH, Azadbakht L. Is Ramadan fasting related to health outcomes? A review on the related evidence. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences. 2014;**19**(10):987

[68] Vasan SK, Karol R, Mahendri N, Arulappan N, Jacob JJ, Thomas N. A prospective assessment of dietary patterns in Muslim subjects with type 2 diabetes who undertake fasting during Ramadan. Indian Journal of Endocrinology and Metabolism. 2012;**16**(4):552

[69] Larijani B, Zahedi F, Sanjari M, Amini M, Jalili R, Adibi H, et al. The effect of Ramadan fasting on fasting serum glucose in healthy adults. Medical Journal of Malaysia. 2003;**58**(5):678-680

[70] Gnanou JV, Caszo BA, Khalil KM, Abdullah SL, Knight VF, Bidin MZ. Effects of Ramadan fasting on glucose homeostasis and adiponectin levels in healthy adult males. Journal of Diabetes and Metabolic Disorders. 2015;**14**:55-55. DOI: 10.1186/ s40200-015-0183-9

[71] Aksungar FB, Sarikaya M, Coskun A, Serteser M, Unsal I. Comparison of intermittent fasting versus caloric restriction in obese subjects: A two year follow-up. The Journal of Nutrition, Health and Aging. 2017;**21**(6):681-685

[72] Bogdan A, Bouchareb B, Touitou Y. Ramadan fasting alters endocrine and neuroendocrine circadian patterns. Meal–time as a synchronizer in humans? Life Sciences. 2001;**68**(14):1607-1615

[73] Salim I, Al Suwaidi J, Ghadban W, Alkilani H, Salam AM. Impact of religious Ramadan fasting on cardiovascular disease: A systematic review of the literature. Current Medical Research and

**125**

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS)*

*DOI: http://dx.doi.org/10.5772/intechopen.89333*

Opinion. 2013;**29**(4):343-354. DOI: 10.1185/03007995.2013.774270

[74] Al-Shafei AI. Ramadan fasting ameliorates arterial pulse pressure and lipid profile, and alleviates oxidative stress in hypertensive patients. Blood Pressure. 2014;**23**(3):160-167. DOI: 10.3109/08037051.2013.836808

[75] Çomoğlu S, Temizhan A,

of Ramadan fasting on stroke. Turkish Journal of Medical Sciences.

Research—JCDR. 2014;**8**(3):16

[77] Topacoglu H, Karcioglu O, Yuruktumen A, Kiran S, Cimrin A, Ozucelik D, et al. Impact of Ramadan on demographics and frequencies of disease-related visits in the emergency department. International Journal of Clinical Practice. 2005;**59**(8):900-905

[78] Bursztyn M, Mekler J, Wachtel N, Ben-Ishay D. Siesta and ambulatory

comparability of the afternoon nap and night sleep. American Journal of Hypertension. 1994;**7**(3):217-221

[79] Chamsi-Pasha H, Ahmed WH, Al-Shaibi KF. The cardiac patient during Ramadan and Hajj. Journal of the Saudi Heart Association. 2014;**26**(4):212-215

blood pressure monitoring

[76] Salahuddin M, Sayed Ashfak A, Syed S, Badaam K. Effect of Ramadan fasting on body weight (BP) and biochemical parameters in middle aged hypertensive subjects: An observational trial. Journal of Clinical and Diagnostic

2003;**33**(4):237-241

Peşinci E, Tandoğan İ, Özbakir Ş. Effects

*The Effect of Ramadan Fasting on Metabolic Syndrome (MetS) DOI: http://dx.doi.org/10.5772/intechopen.89333*

Opinion. 2013;**29**(4):343-354. DOI: 10.1185/03007995.2013.774270

*Blood Glucose Levels*

2015;**31**(5):1250

Medicine. 2018;**17**(4):196

2012;**7**(10):e47615

ajcn/57.5.640

2014;**53**(3):929-942

weight loss in obese subjects in the NUGENOB study: Comparison of bioelectrical impedance vs. dual-energy X-ray absorptiometry. Diabetes and Metabolism. 2011;**37**(3):222-229. DOI: 10.1016/j.diabet.2010.10.007

[67] Rouhani MH, Azadbakht L. Is Ramadan fasting related to health outcomes? A review on the related evidence. Journal of Research in Medical

Sciences: The Official Journal of Isfahan University of Medical Sciences.

[68] Vasan SK, Karol R, Mahendri N, Arulappan N, Jacob JJ, Thomas N. A prospective assessment of dietary patterns in Muslim subjects with type 2 diabetes who undertake fasting during Ramadan. Indian Journal of Endocrinology and Metabolism.

[69] Larijani B, Zahedi F, Sanjari M, Amini M, Jalili R, Adibi H, et al. The effect of Ramadan fasting on fasting serum glucose in healthy adults. Medical Journal of Malaysia. 2003;**58**(5):678-680

Khalil KM, Abdullah SL, Knight VF, Bidin MZ. Effects of Ramadan fasting on glucose homeostasis and adiponectin levels in healthy adult males. Journal of Diabetes and Metabolic Disorders.

[70] Gnanou JV, Caszo BA,

2015;**14**:55-55. DOI: 10.1186/

[71] Aksungar FB, Sarikaya M, Coskun A, Serteser M, Unsal I. Comparison of intermittent fasting versus caloric restriction in obese subjects: A two year follow-up. The Journal of Nutrition, Health and Aging.

[72] Bogdan A, Bouchareb B, Touitou Y. Ramadan fasting alters endocrine and neuroendocrine circadian patterns. Meal–time as a synchronizer in humans? Life Sciences.

2001;**68**(14):1607-1615

[73] Salim I, Al Suwaidi J,

on cardiovascular disease: A systematic review of the literature. Current Medical Research and

Ghadban W, Alkilani H, Salam AM. Impact of religious Ramadan fasting

s40200-015-0183-9

2017;**21**(6):681-685

2014;**19**(10):987

2012;**16**(4):552

[61] Mazidi M, Rezaie P, Chaudhri O, Karimi E, Nematy M. The effect of Ramadan fasting on cardiometabolic risk factors and anthropometrics parameters: A systematic review. Pakistan Journal of Medical Sciences.

[62] Bener A, Al-Hamaq AO, Öztürk M, Çatan F, Haris PI, Rajput KU, et al. Effect of ramadan fasting on glycemic control and other essential variables in diabetic patients. Annals of African

[63] Shehab A, Abdulle A, El Issa A, Al Suwaidi J, Nagelkerke N. Favorable changes in lipid profile: The effects of fasting after Ramadan. PLoS One.

[64] Maislos M, Khamaysi N, Assali A, Abou-Rabiah Y, Zvili I, Shany S. Marked

American Journal of Clinical Nutrition. 1993;**57**(5):640-642. DOI: 10.1093/

healthy population? A meta-analysis. Journal of Religion and Health.

increase in plasma high-densitylipoprotein cholesterol after prolonged

fasting during Ramadan. The

[65] Kul S, Savaş E, Öztürk ZA, Karadağ G. Does Ramadan fasting alter body weight and blood lipids and fasting blood glucose in a

[66] Akturk I, Biyik I, Kocas C, Yalcin A, Erturk M, Uzun F. PP-106 Effects of Ramadan fasting on lipid profile, brain nadriuretic peptide, renal functions and electrolyte levels in patients with hypertension. International Journal of Cardiology.

**124**

2012;**155**:S134

[74] Al-Shafei AI. Ramadan fasting ameliorates arterial pulse pressure and lipid profile, and alleviates oxidative stress in hypertensive patients. Blood Pressure. 2014;**23**(3):160-167. DOI: 10.3109/08037051.2013.836808

[75] Çomoğlu S, Temizhan A, Peşinci E, Tandoğan İ, Özbakir Ş. Effects of Ramadan fasting on stroke. Turkish Journal of Medical Sciences. 2003;**33**(4):237-241

[76] Salahuddin M, Sayed Ashfak A, Syed S, Badaam K. Effect of Ramadan fasting on body weight (BP) and biochemical parameters in middle aged hypertensive subjects: An observational trial. Journal of Clinical and Diagnostic Research—JCDR. 2014;**8**(3):16

[77] Topacoglu H, Karcioglu O, Yuruktumen A, Kiran S, Cimrin A, Ozucelik D, et al. Impact of Ramadan on demographics and frequencies of disease-related visits in the emergency department. International Journal of Clinical Practice. 2005;**59**(8):900-905

[78] Bursztyn M, Mekler J, Wachtel N, Ben-Ishay D. Siesta and ambulatory blood pressure monitoring comparability of the afternoon nap and night sleep. American Journal of Hypertension. 1994;**7**(3):217-221

[79] Chamsi-Pasha H, Ahmed WH, Al-Shaibi KF. The cardiac patient during Ramadan and Hajj. Journal of the Saudi Heart Association. 2014;**26**(4):212-215

### *Edited by Leszek Szablewski*

The main source of energy for the body is glucose. Its low blood concentrations can cause seizures, loss of consciousness and death. Long lasting high glucose levels can cause blindness, renal failure, cardiac and peripheral vascular disease, and neuropathy. Blood glucose concentrations need to be maintained within narrow limits. The process of maintaining blood glucose at a steady state is called glucose homeostasis. This is achieved through a balance of the rate of consumption of dietary carbohydrates, utilization of glucose by peripheral tissues, and the loss of glucose through the kidney tubule. The liver and kidney also play a role in glucose homeostasis. This book aims to provide an overview of blood glucose levels in health and diseases.

Published in London, UK © 2020 IntechOpen © Ugreen / iStock

Blood Glucose Levels

Blood Glucose Levels

*Edited by Leszek Szablewski*