**Inflammation and Hypoglycemia: The Lipid Connection**

### Oren Tirosh

*Institute of Biochemistry, Food Science and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel* 

### **1. Introduction**

Patients can be exposed to a variety of potentially life threatening acute inflammations mainly sepsis, which accounts to 9% of all death in the US. The prevalence of non-alcoholic fatty liver disease (NAFLD) is about 30% in the general population. Fatty liver is known to be more sensitive to endotoxins. It has been reported that metabolic aspects of sepsis and endotoxemia are suppression of the fatty acid beta-oxidation pathway and severe hypoglycemia. This can be due to lipotoxic effects following accumulation of free fatty acids in the liver and suppression of gluconeogenesis. In this chapter we will review the published facts about the development of hypoglycemic effects during sepsis and the possible connection of such an effect to the dysregulation of lipid metabolism. Secondly a possible redox related antilipotoxic cellular mechanism will be suggested. Such mechanism can alleviate the endotoxic hypoglycemic effect and is related to nitric oxide signaling. Nitric oxide signaling has been demonstrated to regulate the metabolic status of cells including upregulation of mitochondrial biogenesis, promoting liver glucose production and depending on the biological setting to protect cells against accumulation of oxidative damage, all possibly protect against development of hypoglycemia following liver injury.

### **2. Non-alcoholic fatty liver disease**

#### **2.1 Introduction**

Non-alcoholic fatty liver disease NAFLD comprises a spectrum of hepatic pathology, ranging from simple steatosis (SS), in which there is an increase of fat accumulation in hepatocytes, through steatohepatitis to cirrhosis (Farrell, GC et al., 2008). Primary NAFLD is associated with obesity, insulin resistance and metabolic syndrome, diabetes and dyslipidemia, while secondary NAFLD is associated with all forms of liver damage including viral infections autoimmune and heradetory disease, drugs, toxins and nutrition (parenteral nutrition , B12/folic acid deficiency etc.) (Musso, G et al., 2010) (Figure 1). Nonalcoholic steatohepatitis (NASH) is a progressive lesion in which steatosis is accompanied by hepatocyte injury and death, as well as hepatic infiltration by inflammatory cells. NASH-related liver damage often triggers liver fibrosis. In severe cases, NASH may progress to cirrhosis and possibly hepatocellular carcinoma (Lim, JH et al., 2006). NAFLD is one of the most common liver diseases worldwide, affecting all racial, ethnic, and age

Inflammation and Hypoglycemia: The Lipid Connection 97

NAFLD is increasingly being recognized as an important and common condition, affecting approximately 20-45% of the general population (Joy, D et al., 2003) in different countries. It is estimated to affect approximately 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome (Rector, RS et al., 2008; Zivkovic, AM et al., 2007). According to (Angulo, P, 2007), NAFLD affects one in three adults and one in 10 children in the United States. Although NAFLD typically occurs between the fourth and six decades of life (Targher, G et al., 2007; Zhou, YJ et al., 2007), it is known to affect children as well as adults and is not considered discriminatory to age (Imhof, A et al., 2007; Zhou, YJ et al., 2007). Many studies have found a wide discrimination of NAFLD between the sexes

Among different ethnic groups, however, the picture becomes a bit more complicated. Browning et al (Browning, JD et al., 2004) reported that the prevalence of fatty liver was highest in Hispanics (45%) compared to Caucasians (33%) or African Americans (24%) which introduced the possibility of race related variability in the susceptibility to NAFLD. Furthermore, within specific race, such as Caucasians, sex-related differences in the presence of fatty liver (42% in men and 24% in women) had been observed, which indicates the risk factors for NAFLD may vary depending on ethnicity and sex (Browning et al, 2004). Among 3543 peoples, surveyed in South China, 609 (17.2%) were diagnosed having fatty liver disease (FLD, 23.0% in urban and 14.5% in rural) out of which prevalence of NAFLD was 15.5% (Zhou, YJ et al., 2007). In the same study, prevalence of FLD among the children at the age of 7-18 years was 1.3% with all having NAFLD. The prevalence and incidence of NAFLD is expected to increase worldwide as the global obesity epidemic spreads and the trend in developing countries toward the western lifestyle continues (Angulo, P, 2007).

Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis (Angulo, P & KD Lindor, 2002). NAFLD has been characterized with asymptomatic elevation of aminotransferases, radiological findings of fatty liver or unexplained persistent hepatomegaly (Angulo, P & KD Lindor, 2002). NAFLD patients may be complaint of fatigue or a sensation of fullness or discomfort in the right upper abdomen . Hepatomegaly is one of the more consistent physical findings, described in up to 75% of patients with NAFLD (Yan, E et al., 2007). Other findings on physical examination that may suggest NAFLD as the cause of liver abnormalities include those characterizing insulin resistance and metabolic syndrome, such as central obesity, hypertriglyceridemia, and

The most common and often the only laboratory abnormality found in NAFLD patients, is mild to moderate elevation of liver enzymes (Angulo, P, 2007; Angulo, P & KD Lindor, 2002) alanine aminotransferase (ALT) and aspartate aminotransferase (AST): defined as ALT>45 U/L, AST>45 U/L or γ Glutamyl transferase (GGT) >50 U/L (Hickman, I et al., 2008)In the patients with FLD, AST/ALT ratio is usually less than one, but this ratio increases as fibrosis advances (Angulo, P, 2007). A study on Japanese adults showed that triglycerides, total protein albumin, AST and ALT were all significantly higher while high density lipoprotein (HDL) cholesterol and AST/ALT ratio were significantly lower in subjects with NAFLD

(Amarapurkar, D et al., 2007; Zelber-Sagi, S et al., 2006).

**2.3 Clinical aspects of NAFLD** 

hypertension (Yan, E et al., 2007).

than those without fatty liver (Jimba, S et al., 2005).

**2.2 Epidemiology** 

groups without sex predilection. The prevalence of NAFLD is around 30 % of the general population (Musso, G et al., 2009; Musso, G et al., 2010), NASH affects about 3 percent of the lean population (those weighing less than 110 percent of their ideal body weight), 19 percent of the obese population, and almost half of morbidly obese people. It is estimated about that 8.6 million obese adult Americans may have NASH and about 30.1 million may have the simple steatosis. Thus, the very high prevalence of fatty liver means that this disorder will contribute significantly to an increased burden of ill-health at the present and in the future (Farrell, GC et al., 2008).

NAFLD refers to the presence of hepatic stetosis not associated with a significant intake of alcohol (Adams, LA & KD Lindor, 2007) and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide (Yan, E et al., 2007). When fat accounts for more than 10% of liver's weight, then the condition is called fatty liver and it can develop more serious complications (American Liver Foundation). Fatty liver may cause no damage, but the excess fat leads to inflammation causing liver damage is refered to as steatohepatitis (American Liver Foundation). The term nonalcoholic steatohepatitis (NASH) was first coined by Ludwig et al at 1980 (Ludwig, J et al., 1980) describing the pathology of 20 patients histologically similar with alcoholic hepatitis but without the history of alcohol abuse. Sometimes, inflammation from a fatty liver is linked to alcohol abuse; this is known as alcoholic steatohepatitis (ASH). Otherwise the condition is called NASH (American Liver Foundation). NAFLD comprises a spectrum of liver pathology including bland steatosis, steatohepatitis, cirrhosis (Yang, L & A Diehl, 2007) and hepatocellular carcinoma (Angulo, P, 2007) where most liver related morbidity and mortality occur. The histological damage in NAFLD is very similar to that seen in patients with alcoholic liver disease (ALD), but NAFLD is by definition not alcohol induced (Angulo, P, 2007).

NAFLD is the most common chronic liver disease in the western world (Adams, LA & KD Lindor, 2007). Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries, subsequently increasing the risk for developing the metabolic syndrome and NAFLD (Rector, RS et al., 2008). Although, NAFLD may be categorized as primary and secondary depending on the underlying pathogenesis both type of NAFLD can be interrelated (Figure 1).

Fig. 1. Type and causes of NAFLD. Primary and secondary NAFLD may be interrelated. Induction of liver damage with may lead to fat accumulation in the liver may exacerbate primary NAFLD under conditions of hyperlipidemic, on the other hand primary NAFLD can increase the vulnerability of the liver to different kind of stressors and damaging agents.

#### **2.2 Epidemiology**

96 Diabetes – Damages and Treatments

groups without sex predilection. The prevalence of NAFLD is around 30 % of the general population (Musso, G et al., 2009; Musso, G et al., 2010), NASH affects about 3 percent of the lean population (those weighing less than 110 percent of their ideal body weight), 19 percent of the obese population, and almost half of morbidly obese people. It is estimated about that 8.6 million obese adult Americans may have NASH and about 30.1 million may have the simple steatosis. Thus, the very high prevalence of fatty liver means that this disorder will contribute significantly to an increased burden of ill-health at the present and in the future

NAFLD refers to the presence of hepatic stetosis not associated with a significant intake of alcohol (Adams, LA & KD Lindor, 2007) and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide (Yan, E et al., 2007). When fat accounts for more than 10% of liver's weight, then the condition is called fatty liver and it can develop more serious complications (American Liver Foundation). Fatty liver may cause no damage, but the excess fat leads to inflammation causing liver damage is refered to as steatohepatitis (American Liver Foundation). The term nonalcoholic steatohepatitis (NASH) was first coined by Ludwig et al at 1980 (Ludwig, J et al., 1980) describing the pathology of 20 patients histologically similar with alcoholic hepatitis but without the history of alcohol abuse. Sometimes, inflammation from a fatty liver is linked to alcohol abuse; this is known as alcoholic steatohepatitis (ASH). Otherwise the condition is called NASH (American Liver Foundation). NAFLD comprises a spectrum of liver pathology including bland steatosis, steatohepatitis, cirrhosis (Yang, L & A Diehl, 2007) and hepatocellular carcinoma (Angulo, P, 2007) where most liver related morbidity and mortality occur. The histological damage in NAFLD is very similar to that seen in patients with alcoholic liver disease (ALD), but

NAFLD is the most common chronic liver disease in the western world (Adams, LA & KD Lindor, 2007). Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries, subsequently increasing the risk for developing the metabolic syndrome and NAFLD (Rector, RS et al., 2008). Although, NAFLD may be categorized as primary and secondary depending on the underlying pathogenesis both type

Fig. 1. Type and causes of NAFLD. Primary and secondary NAFLD may be interrelated. Induction of liver damage with may lead to fat accumulation in the liver may exacerbate primary NAFLD under conditions of hyperlipidemic, on the other hand primary NAFLD can increase the vulnerability of the liver to different kind of stressors and damaging agents.

NAFLD is by definition not alcohol induced (Angulo, P, 2007).

of NAFLD can be interrelated (Figure 1).

(Farrell, GC et al., 2008).

NAFLD is increasingly being recognized as an important and common condition, affecting approximately 20-45% of the general population (Joy, D et al., 2003) in different countries. It is estimated to affect approximately 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome (Rector, RS et al., 2008; Zivkovic, AM et al., 2007). According to (Angulo, P, 2007), NAFLD affects one in three adults and one in 10 children in the United States. Although NAFLD typically occurs between the fourth and six decades of life (Targher, G et al., 2007; Zhou, YJ et al., 2007), it is known to affect children as well as adults and is not considered discriminatory to age (Imhof, A et al., 2007; Zhou, YJ et al., 2007). Many studies have found a wide discrimination of NAFLD between the sexes (Amarapurkar, D et al., 2007; Zelber-Sagi, S et al., 2006).

Among different ethnic groups, however, the picture becomes a bit more complicated. Browning et al (Browning, JD et al., 2004) reported that the prevalence of fatty liver was highest in Hispanics (45%) compared to Caucasians (33%) or African Americans (24%) which introduced the possibility of race related variability in the susceptibility to NAFLD. Furthermore, within specific race, such as Caucasians, sex-related differences in the presence of fatty liver (42% in men and 24% in women) had been observed, which indicates the risk factors for NAFLD may vary depending on ethnicity and sex (Browning et al, 2004). Among 3543 peoples, surveyed in South China, 609 (17.2%) were diagnosed having fatty liver disease (FLD, 23.0% in urban and 14.5% in rural) out of which prevalence of NAFLD was 15.5% (Zhou, YJ et al., 2007). In the same study, prevalence of FLD among the children at the age of 7-18 years was 1.3% with all having NAFLD. The prevalence and incidence of NAFLD is expected to increase worldwide as the global obesity epidemic spreads and the trend in developing countries toward the western lifestyle continues (Angulo, P, 2007).

#### **2.3 Clinical aspects of NAFLD**

Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis (Angulo, P & KD Lindor, 2002). NAFLD has been characterized with asymptomatic elevation of aminotransferases, radiological findings of fatty liver or unexplained persistent hepatomegaly (Angulo, P & KD Lindor, 2002). NAFLD patients may be complaint of fatigue or a sensation of fullness or discomfort in the right upper abdomen . Hepatomegaly is one of the more consistent physical findings, described in up to 75% of patients with NAFLD (Yan, E et al., 2007). Other findings on physical examination that may suggest NAFLD as the cause of liver abnormalities include those characterizing insulin resistance and metabolic syndrome, such as central obesity, hypertriglyceridemia, and hypertension (Yan, E et al., 2007).

The most common and often the only laboratory abnormality found in NAFLD patients, is mild to moderate elevation of liver enzymes (Angulo, P, 2007; Angulo, P & KD Lindor, 2002) alanine aminotransferase (ALT) and aspartate aminotransferase (AST): defined as ALT>45 U/L, AST>45 U/L or γ Glutamyl transferase (GGT) >50 U/L (Hickman, I et al., 2008)In the patients with FLD, AST/ALT ratio is usually less than one, but this ratio increases as fibrosis advances (Angulo, P, 2007). A study on Japanese adults showed that triglycerides, total protein albumin, AST and ALT were all significantly higher while high density lipoprotein (HDL) cholesterol and AST/ALT ratio were significantly lower in subjects with NAFLD than those without fatty liver (Jimba, S et al., 2005).

Inflammation and Hypoglycemia: The Lipid Connection 99

stress, or prolonged exercise that overwhelms the ability of mitochondria to oxidize fatty acids. Depending on the specific genetic defect, patients develop fasting hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, liver dysfunction, or sudden death (Kompare, M & WB Rizzo, 2008). Medium-chain acyl-CoA deshydrogenase (MCAD) deficiency is the most frequent disorder of mitochondrial fatty acid oxidation (Baruteau, J et al., 2009), The pathophysiology of these diseases is still not completely understood, hampering optimal treatment (Houten, SM & RJ Wanders). Hypoglycemia as one major clinical sign in all fatty acid oxidation defects and occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake (Spiekerkoetter, U & PA Wood). A connection of such disorders-phenotype with metabolic derangement that are not necessarily related to genetic defected has been demonstrated recently via the Sirtuins. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting (Hirschey, MD et al.).

The liver is known for its regenerative capacity. It is now well accepted that there are two physiological forms of regeneration in the liver as responses to different types of liver injury. The first line for regeneration are mature, normally quiescent adult hepatocytes. During mild liver injury due to drugs, toxins, resection, or acute viral diseases, hepatocytes are the main cell type to proliferate and regenerate the liver. The mature hepatocytes have relatively low proliferative capacity. The second line of defense are the progenitor cell population, that are activated when injury is severe, or when the mature hepatocytes can no longer regenerate the liver due to senescence or arrest (Riehle, KJ et al., 2011). The metabolic requirements of the generating liver form Partial hepatectomy (PH) of from liver damage are impressive. There is a need to activate Kupffer cells in order to initiate the regenerating cascade. For these reasons increased accumulation of insulin independent glucose utilization is needed which may cause plasma glucose utilization due to the high metabolic demend. Impaired regenerative capacity of fatty livers might promote the progression of nonalcoholic fatty liver disease (NAFLD). Partial hepatectomy (PH) activats oxidant-sensitive, growth-regulatory kinase cascades which is abnormal in fatty hepatocytes. The normal coordinated induction of Jun N-terminal kinases (Jnks) and extracellular regulated kinases (Erks) does not occur after PH in ob/ob mice. This is associated with enhanced activation of Akt, which inhibits phosphoenolpyruvate carboxykinase (PEPCK) induction, causing severe hypoglycemia and increased lethality in the

The liver breaks down alcohol so that it can be eliminated from our body. When alcohol is over consumed than the liver can process, the resulting imbalance can injure the liver by interfering with its normal breakdown of proteins, fats, and carbohydrates (American Liver Foundation). ALD is a common consequence of long term alcohol abuse (Zeng, MD et al., 2008) and represents a major cause of mortality and morbidity worldwide (Albano, E, 2008; Bergheim, I et al., 2005). ALD encompasses a broad spectrum of morphological features ranging from simple steatosis with minimal injury to more advanced stage liver injury, including alcoholic steatohepatitis, alcoholic fibrosis and alcoholic cirrhosis (Albano, E, 2008;

**3.2 Liver regeneration** 

ob/ob group (Yang, SQ et al., 2001).

**4. Alcoholic liver injury** 

**4.1 Introduction** 

### **3. Association of fatty liver with hypoglycemia**

### **3.1 Fatty acid oxidation defects**

Adipocytes have the unique capacity to store excess fatty acids in the form of TGs in lipid droplets. Non-adipose tissues, such as hepatocytes, cardiac myocytes and pancreatic beta-cells, have a limited capacity for lipid storage. In hyperlipidemic states, the accumulation of excess lipid in non-adipose tissues can lead to cellular dysfunction and/or cell death, a phenomenon known as lipotoxicity (Listenberger, LL et al., 2003; Unger, RH, 1995; Weinberg, JM, 2006). Most studies attribute strong lipiotoxic effects to free fatty acids (FFAs). Lipotoxic effects in the liver include disruption of liver-cell function (Alkhouri, N et al., 2009).

The connection between increased levels of fatty acids to hypoglycemia is known in genetic diseases of fatty acid oxidation defects (Figure 2). Inherited defects in mitochondrial fattyacid beta-oxidation comprise a group of at least 12 diseases characterized by distinct enzyme or transporter deficiencies. Most of these diseases have a variable age of onset and clinical severity. Symptoms are often episodic and associated with mild viral illness, physiologic

Fig. 2. Classical theory of how biochemical fatty acid oxidation defects generate hypoglycemic phenotype

stress, or prolonged exercise that overwhelms the ability of mitochondria to oxidize fatty acids. Depending on the specific genetic defect, patients develop fasting hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, liver dysfunction, or sudden death (Kompare, M & WB Rizzo, 2008). Medium-chain acyl-CoA deshydrogenase (MCAD) deficiency is the most frequent disorder of mitochondrial fatty acid oxidation (Baruteau, J et al., 2009), The pathophysiology of these diseases is still not completely understood, hampering optimal treatment (Houten, SM & RJ Wanders). Hypoglycemia as one major clinical sign in all fatty acid oxidation defects and occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake (Spiekerkoetter, U & PA Wood). A connection of such disorders-phenotype with metabolic derangement that are not necessarily related to genetic defected has been demonstrated recently via the Sirtuins. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting (Hirschey, MD et al.).

#### **3.2 Liver regeneration**

98 Diabetes – Damages and Treatments

Adipocytes have the unique capacity to store excess fatty acids in the form of TGs in lipid droplets. Non-adipose tissues, such as hepatocytes, cardiac myocytes and pancreatic beta-cells, have a limited capacity for lipid storage. In hyperlipidemic states, the accumulation of excess lipid in non-adipose tissues can lead to cellular dysfunction and/or cell death, a phenomenon known as lipotoxicity (Listenberger, LL et al., 2003; Unger, RH, 1995; Weinberg, JM, 2006). Most studies attribute strong lipiotoxic effects to free fatty acids (FFAs). Lipotoxic effects in the

The connection between increased levels of fatty acids to hypoglycemia is known in genetic diseases of fatty acid oxidation defects (Figure 2). Inherited defects in mitochondrial fattyacid beta-oxidation comprise a group of at least 12 diseases characterized by distinct enzyme or transporter deficiencies. Most of these diseases have a variable age of onset and clinical severity. Symptoms are often episodic and associated with mild viral illness, physiologic

gluconeogenesis

Fig. 2. Classical theory of how biochemical fatty acid oxidation defects generate

defects

Acyl-CoA

Acyl-CoA (-2c)

Acetyl-CoA

TCA cycle

Fatty acid oxidation

**3. Association of fatty liver with hypoglycemia** 

Glucose 6 phosphate

Plasma

Glucose

hypoglycemia

Fatty acid

hypoglycemic phenotype

Acyl-CoA

liver include disruption of liver-cell function (Alkhouri, N et al., 2009).

Lipid droplets formation

(fatty liver)

**3.1 Fatty acid oxidation defects** 

The liver is known for its regenerative capacity. It is now well accepted that there are two physiological forms of regeneration in the liver as responses to different types of liver injury. The first line for regeneration are mature, normally quiescent adult hepatocytes. During mild liver injury due to drugs, toxins, resection, or acute viral diseases, hepatocytes are the main cell type to proliferate and regenerate the liver. The mature hepatocytes have relatively low proliferative capacity. The second line of defense are the progenitor cell population, that are activated when injury is severe, or when the mature hepatocytes can no longer regenerate the liver due to senescence or arrest (Riehle, KJ et al., 2011). The metabolic requirements of the generating liver form Partial hepatectomy (PH) of from liver damage are impressive. There is a need to activate Kupffer cells in order to initiate the regenerating cascade. For these reasons increased accumulation of insulin independent glucose utilization is needed which may cause plasma glucose utilization due to the high metabolic demend. Impaired regenerative capacity of fatty livers might promote the progression of nonalcoholic fatty liver disease (NAFLD). Partial hepatectomy (PH) activats oxidant-sensitive, growth-regulatory kinase cascades which is abnormal in fatty hepatocytes. The normal coordinated induction of Jun N-terminal kinases (Jnks) and extracellular regulated kinases (Erks) does not occur after PH in ob/ob mice. This is associated with enhanced activation of Akt, which inhibits phosphoenolpyruvate carboxykinase (PEPCK) induction, causing severe hypoglycemia and increased lethality in the ob/ob group (Yang, SQ et al., 2001).

#### **4. Alcoholic liver injury**

#### **4.1 Introduction**

The liver breaks down alcohol so that it can be eliminated from our body. When alcohol is over consumed than the liver can process, the resulting imbalance can injure the liver by interfering with its normal breakdown of proteins, fats, and carbohydrates (American Liver Foundation). ALD is a common consequence of long term alcohol abuse (Zeng, MD et al., 2008) and represents a major cause of mortality and morbidity worldwide (Albano, E, 2008; Bergheim, I et al., 2005). ALD encompasses a broad spectrum of morphological features ranging from simple steatosis with minimal injury to more advanced stage liver injury, including alcoholic steatohepatitis, alcoholic fibrosis and alcoholic cirrhosis (Albano, E, 2008;

Inflammation and Hypoglycemia: The Lipid Connection 101

adenine dinucleotide (NADH) is produced due to alcohol metabolism leading to high NADH/NAD+ ratio which overrides the cell's ability to maintain normal redox state (Hasse,

The lactic acid cannot be converted into pyruvate due to lack of NAD+ leading to hyperlacticacedemia (Hasse and Matarese, 2004). They also reported that tricarboxylic acid cycle (TCA) is also diminished because; in one hand it requires a lot of NAD+ and on the other hand the excess NADH inhibits two regulatory enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, as a consequence acetyl coenzyme A (CoA) is accumulated. The mitochondria in turn use hydrogen produced from the ethanol metabolism as a fuel source and all these activities lead to decreased fatty acid oxidation and accumulation of triglycerides in the hepatocytes (Hasse, J & L Matarese, 2004). They also reported that malnutrition can also occur in early alcoholic liver disease due to the suppression of TCA

Mitochondria

Acetaldehyde dehydrogenase (ALDH) Fig. 4. Ethanol metabolism in hepatocytes. These mechanisms are potentially involved in oxidative stress production. Ethanol is metabolized in acetaldehyde and then transformed

Chronic ethanol consumption increases fatty acid synthesis by inducing the expression of lipogenic enzymes which are regulated by transcription factor SREBP (Adachi, M & DA Brenner, 2005). Chronic ethanol consumption significantly inhibits mitochondrial ALDH

peroxisome

Acetaldehyde

Alcohol

H2O2 + catalase

Acetaldehyde

Acetate

)]. High reduced nicotinamide

Cytosol

Acetaldehyde

Alcohol

Moderate alcohol consumption Alcohol dehydrogenase ALD pathway

hydrogen peroxides (H2O2) and super oxide anion (O2-

cycle coupled with decreased gluconeogenesis due to ethanol.

J & L Matarese, 2004).

Endoplasmic reticulum

Acetaldehyde

Heavy alcohol consumption,

the MEOS pathway

into acetate, as shown.

Alcohol

Zeng, MD et al., 2008). The risk of steatosis, inflammation and fibrosis are more common in alcoholics and increases with time and the amount of ethanol consumed (Vidali, M et al., 2008).

### **4.2 Clinical aspects of ALD**

Fatty liver, the most common syndrome of ALD, is characterized by the excessive accumulation of fat inside hepatocytes (Adachi, M & DA Brenner, 2005). Indeed the excessive fat accumulation in the hepatocytes is the most common and earliest response of the liver to chronic alcohol consumption (Song, Z et al., 2008). Morphological criteria of steatohepatitis are steatosis, ballooning of hepatocytes, pericellular fibrosis and inflammation (Denk, H et al., 2005). In an animal model of ALD, rats exposed 4 weeks to alcohol exhibited a significant increase in liver to body weight ratio, serum ALT levels and hepatic TNF- α compared to control group (Song, Z et al., 2008). Tabassum, F et al. (Tabassum, F et al., 2001) found that the levels of alkaline phosphate, ALT, protein and globulin were significantly increased in alcoholic males compared to control subjects. The AST/ALT ratio is significantly higher in ALD patients sometimes even higher than two (Adachi, M & DA Brenner, 2005).

#### **4.3 Ethanol metabolism and role of acetaldehyde**

There are multiple mechanisms for the development and progression of ALD (Figure 3) and many of these mechanisms interact to each other (Barve, A et al., 2008).

Fig. 3. Mechanisms for the development of non-alcoholic fatty liver disease

ALD has a complex pathogenesis, in which acetaldehyde; the major ethanol metabolite plays a central role (Lieber, CS, 1997). Alcohol is primarily metabolized by the successive oxidative activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), Figure 4, (Hasse, J & L Matarese, 2004; Lumeng, L & DW Crabb, 2001). Ethanol is metabolized mainly in the hepatocytes in three different sites: cytosol, endoplasmic reticulum, peroxisome and mitochondria (De Minicis, S & DA Brenner, 2008). According to (Lieber, CS, 1997) the main pathway involves cytoplasmic ADH which catalyzes the oxidation of ethanol to acetaldehyde then oxidized to acetate by the mitochondrial ALDH. Most of acetate is released into the blood (Hasse, J & L Matarese, 2004). According to Novitskiy, G *et al* (Novitskiy, G et al., 2006) acetaldehyde enhances the formation of ROS. According to (Lieber, CS, 1997), sever toxic manifestations are produced by an accessory inducible pathway, the microsomal ethanol-oxidizing system (MEOS) in endoplasmic reticulum involving an ethanol-inducible CYP2E1 in which the oxidation of ethanol to acetaldehyde and acetate also leads to generation of ROS [hydroxyethyl free radicals,

Zeng, MD et al., 2008). The risk of steatosis, inflammation and fibrosis are more common in alcoholics and increases with time and the amount of ethanol consumed (Vidali, M et al.,

Fatty liver, the most common syndrome of ALD, is characterized by the excessive accumulation of fat inside hepatocytes (Adachi, M & DA Brenner, 2005). Indeed the excessive fat accumulation in the hepatocytes is the most common and earliest response of the liver to chronic alcohol consumption (Song, Z et al., 2008). Morphological criteria of steatohepatitis are steatosis, ballooning of hepatocytes, pericellular fibrosis and inflammation (Denk, H et al., 2005). In an animal model of ALD, rats exposed 4 weeks to alcohol exhibited a significant increase in liver to body weight ratio, serum ALT levels and hepatic TNF- α compared to control group (Song, Z et al., 2008). Tabassum, F et al. (Tabassum, F et al., 2001) found that the levels of alkaline phosphate, ALT, protein and globulin were significantly increased in alcoholic males compared to control subjects. The AST/ALT ratio is significantly higher in ALD patients sometimes even higher than two

There are multiple mechanisms for the development and progression of ALD (Figure 3) and

Altered methionine metabolism Inflammation and cytokines Nutritional abnormalities

Mitochondrial dysfunction

ALD has a complex pathogenesis, in which acetaldehyde; the major ethanol metabolite plays a central role (Lieber, CS, 1997). Alcohol is primarily metabolized by the successive oxidative activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), Figure 4, (Hasse, J & L Matarese, 2004; Lumeng, L & DW Crabb, 2001). Ethanol is metabolized mainly in the hepatocytes in three different sites: cytosol, endoplasmic reticulum, peroxisome and mitochondria (De Minicis, S & DA Brenner, 2008). According to (Lieber, CS, 1997) the main pathway involves cytoplasmic ADH which catalyzes the oxidation of ethanol to acetaldehyde then oxidized to acetate by the mitochondrial ALDH. Most of acetate is released into the blood (Hasse, J & L Matarese, 2004). According to Novitskiy, G *et al* (Novitskiy, G et al., 2006) acetaldehyde enhances the formation of ROS. According to (Lieber, CS, 1997), sever toxic manifestations are produced by an accessory inducible pathway, the microsomal ethanol-oxidizing system (MEOS) in endoplasmic reticulum involving an ethanol-inducible CYP2E1 in which the oxidation of ethanol to acetaldehyde and acetate also leads to generation of ROS [hydroxyethyl free radicals,

Alcoholic Liver disease

2008).

**4.2 Clinical aspects of ALD** 

(Adachi, M & DA Brenner, 2005).

Alcohol consumption

**4.3 Ethanol metabolism and role of acetaldehyde** 

many of these mechanisms interact to each other (Barve, A et al., 2008).

Genetics

Fig. 3. Mechanisms for the development of non-alcoholic fatty liver disease

Oxidative stress

Altered immunity Proteosome dysfunction hydrogen peroxides (H2O2) and super oxide anion (O2 - )]. High reduced nicotinamide adenine dinucleotide (NADH) is produced due to alcohol metabolism leading to high NADH/NAD+ ratio which overrides the cell's ability to maintain normal redox state (Hasse, J & L Matarese, 2004).

The lactic acid cannot be converted into pyruvate due to lack of NAD+ leading to hyperlacticacedemia (Hasse and Matarese, 2004). They also reported that tricarboxylic acid cycle (TCA) is also diminished because; in one hand it requires a lot of NAD+ and on the other hand the excess NADH inhibits two regulatory enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, as a consequence acetyl coenzyme A (CoA) is accumulated. The mitochondria in turn use hydrogen produced from the ethanol metabolism as a fuel source and all these activities lead to decreased fatty acid oxidation and accumulation of triglycerides in the hepatocytes (Hasse, J & L Matarese, 2004). They also reported that malnutrition can also occur in early alcoholic liver disease due to the suppression of TCA cycle coupled with decreased gluconeogenesis due to ethanol.

Fig. 4. Ethanol metabolism in hepatocytes. These mechanisms are potentially involved in oxidative stress production. Ethanol is metabolized in acetaldehyde and then transformed into acetate, as shown.

Chronic ethanol consumption increases fatty acid synthesis by inducing the expression of lipogenic enzymes which are regulated by transcription factor SREBP (Adachi, M & DA Brenner, 2005). Chronic ethanol consumption significantly inhibits mitochondrial ALDH

Inflammation and Hypoglycemia: The Lipid Connection 103

uninterrupted drinking often with little dietary intake. Most of these individuals suffered from severe hypoglycemia. The common hepatic pathology was the extensive appearance of numerous microvesicular fatty droplets in the hepatocytes together with varying degrees of macrovesicular fatty change; four subjects had an underlying cirrhosis. Death undoubtedly results from a variety of metabolic disturbances triggered by the combination of massive ethanol intake and starvation. The appearance of extensive microvesicular fatty change superimposed on macrovesicular fatty change was considered to be an associated phenomenon. The most striking findings in the liver were extensive microvesicular fatty

Ischemic hepatitis also known Hypoxic hepatitis or shock liver, can be characterized by necrosis of the zone 3 hepatocytes and significant increase in serum aminotransferase levels. It is the consequence of multiorgan injury. Outcome is influenced by the severity of liver impairment and the etiology and severity of the basic disease (Fuhrmann, V et al., 2009).The syndrome occurs under conditions of clinical setting of cardiac, circulatory or respiratory failure. It is recognized as the most frequent cause of acute liver injury with a reported prevalence of up to 10% in the intensive care unit (Fuhrmann, V et al., 2010). Patients with ischemic hepatitis and vasopressor therapy have a significantly increased mortality risk in the medical intensive care unit population. Ischemic hepatitis causes several complications including spontaneous hypoglycemia which can be considered secondary to impairment of gluconeogenic response in the exhausted liver (Fuhrmann, V et al., 2010; Fuhrmann, V et al.,

Definition "Systemic Inflammatory Response Syndrome or **(SIRS)** is evidence of the body's ongoing inflammatory response. When SIRS is suspected or known to be caused by an infection, this is sepsis. Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing, coagulation or other blood abnormalities, decreased urine production, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis), this is septic shock. Sepsis can lead to multiple organ dysfunction syndrome (MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse

Sepsis can be defined as the body's response to an infection. An infection is caused by microorganisms or bacteria invading the body and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis is acquired quickest with infections

Bacteremia is the presence of viable bacteria in the bloodstream. Likewise, the terms viremia and fungemia simply refer to viruses and fungi in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental

developed in surgery and physical contact with someone with sepsis.

change within hepatocyte and the presence of megamitochondria.

**6. Ischemic hepatitis** 

2009; Nomura, T et al., 2009).

intravascular coagulation, among other things.

**7. Sepsis** 

**7.1 Introduction** 

activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in striking increase in tissue and plasma levels of acetaldehyde which results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver (Lieber, CS, 1997). However, in many cases Alcohol consumption can generate a life threatening hypoglycemia.

### **5. ALD and hypoglycemia**

Alcohol consumption may have beneficial as well as deadly consequences. It is generally considered that alcohol consumption interferes with all three glucose sources and with the actions of the regulatory hormones. Chronic heavy drinkers often have insufficient dietary intake of glucose. Without eating, glycogen stores are exhausted in a few hours (Gordon, GG & CS Lieber, 1992). In addition, the body's glucose production is inhibited while alcohol is being metabolized (Sneyd, JGT, 1989). The combination of these effects can cause severe hypoglycemia 6 to 36 hours after the drinking episode (1). Even in well-nourished people, alcohol can disturb blood sugar levels. Acute alcohol consumption, especially in combination with sugar, augments insulin secretion and causes temporary hypoglycemia (O'Keefe, SJ & V Marks, 1977). In addition, studies in healthy subjects and insulin-dependent diabetics have shown that acute alcohol consumption can impair the hormonal response to hypoglycemia. Alcohol consumption can be especially harmful in people with a predisposition to hypoglycemia, such as patients who are being treated for diabetes. Alcohol can interfere with the management of diabetes in different ways. Acute as well as chronic alcohol consumption can alter the effectiveness of hypoglycemic medications. Treatment of diabetes by tight control of blood glucose levels is difficult in alcoholics, and both hypoglycemic and hyperglycemic episodes are common. In a Japanese study, alcoholics with diabetes had a significantly lower survival rate than other alcoholics (Judith Fradkin, MD, 1994). A recent meta analysis indicated beneficial effect of moderate alcohol consumption reduces the incidence of type 2 diabetes (T2D), however, binge drinking seems to increase the incidence. Acute intake of alcohol does not increase risk of hypoglycemia in diet treated subjects with T2D, only when sulphonylurea is co-administered. Long-term alcohol use seems to be associated with improved glycemic control in T2D probably due to improved insulin sensitivity (Pietraszek, A et al., 2010). The capacity of alcohol to shift its activity from beneficial to deleterious could be related to other factors that are related to impairment in lipid metabolism.

ALD has been suspected known to generate the sudden death syndrome in alcoholic individuals. Two major factors have been considered contributory to ethanol-induced hypoglycaemia (Arky, RA & N Freinkel, 1966; Madison, LL, 1968) suppression of hepatic gluconeogenesis resulting from an increase in the NADH/NAD+ ratio accompanied by enhanced ethanol metabolism, and depletion of hepatic glycogen storage secondary to starvation. In cases of alcohol-related sudden deaths hydroxybutyrate levels are significantly elevated. Platia and Hsu (Platia, EV & TH Hsu, 1979)) described five nondiabetic alcohol abusers with hypoglycaemic coma and ketoacidosis and contended that the combination of alcohol-related hypoglycaemia and ketoacidosis may be common.

Part of the pathogenesis of the widely known syndrome of sudden death with hepatic fatty metamorphosis observed in alcohol abusers was described by Yuzuriha *et al*. (Yuzuriha, T et al., 1997), 11 subjects who died under such circumstances between 1987 and 1993 were scrutinized both for clinical and pathological data. Death occurred followed several days of uninterrupted drinking often with little dietary intake. Most of these individuals suffered from severe hypoglycemia. The common hepatic pathology was the extensive appearance of numerous microvesicular fatty droplets in the hepatocytes together with varying degrees of macrovesicular fatty change; four subjects had an underlying cirrhosis. Death undoubtedly results from a variety of metabolic disturbances triggered by the combination of massive ethanol intake and starvation. The appearance of extensive microvesicular fatty change superimposed on macrovesicular fatty change was considered to be an associated phenomenon. The most striking findings in the liver were extensive microvesicular fatty change within hepatocyte and the presence of megamitochondria.

### **6. Ischemic hepatitis**

102 Diabetes – Damages and Treatments

activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in striking increase in tissue and plasma levels of acetaldehyde which results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver (Lieber, CS, 1997). However, in many cases Alcohol consumption can generate a life

Alcohol consumption may have beneficial as well as deadly consequences. It is generally considered that alcohol consumption interferes with all three glucose sources and with the actions of the regulatory hormones. Chronic heavy drinkers often have insufficient dietary intake of glucose. Without eating, glycogen stores are exhausted in a few hours (Gordon, GG & CS Lieber, 1992). In addition, the body's glucose production is inhibited while alcohol is being metabolized (Sneyd, JGT, 1989). The combination of these effects can cause severe hypoglycemia 6 to 36 hours after the drinking episode (1). Even in well-nourished people, alcohol can disturb blood sugar levels. Acute alcohol consumption, especially in combination with sugar, augments insulin secretion and causes temporary hypoglycemia (O'Keefe, SJ & V Marks, 1977). In addition, studies in healthy subjects and insulin-dependent diabetics have shown that acute alcohol consumption can impair the hormonal response to hypoglycemia. Alcohol consumption can be especially harmful in people with a predisposition to hypoglycemia, such as patients who are being treated for diabetes. Alcohol can interfere with the management of diabetes in different ways. Acute as well as chronic alcohol consumption can alter the effectiveness of hypoglycemic medications. Treatment of diabetes by tight control of blood glucose levels is difficult in alcoholics, and both hypoglycemic and hyperglycemic episodes are common. In a Japanese study, alcoholics with diabetes had a significantly lower survival rate than other alcoholics (Judith Fradkin, MD, 1994). A recent meta analysis indicated beneficial effect of moderate alcohol consumption reduces the incidence of type 2 diabetes (T2D), however, binge drinking seems to increase the incidence. Acute intake of alcohol does not increase risk of hypoglycemia in diet treated subjects with T2D, only when sulphonylurea is co-administered. Long-term alcohol use seems to be associated with improved glycemic control in T2D probably due to improved insulin sensitivity (Pietraszek, A et al., 2010). The capacity of alcohol to shift its activity from beneficial to deleterious could be related to other factors that are related to

ALD has been suspected known to generate the sudden death syndrome in alcoholic individuals. Two major factors have been considered contributory to ethanol-induced hypoglycaemia (Arky, RA & N Freinkel, 1966; Madison, LL, 1968) suppression of hepatic gluconeogenesis resulting from an increase in the NADH/NAD+ ratio accompanied by enhanced ethanol metabolism, and depletion of hepatic glycogen storage secondary to starvation. In cases of alcohol-related sudden deaths hydroxybutyrate levels are significantly elevated. Platia and Hsu (Platia, EV & TH Hsu, 1979)) described five nondiabetic alcohol abusers with hypoglycaemic coma and ketoacidosis and contended that the

Part of the pathogenesis of the widely known syndrome of sudden death with hepatic fatty metamorphosis observed in alcohol abusers was described by Yuzuriha *et al*. (Yuzuriha, T et al., 1997), 11 subjects who died under such circumstances between 1987 and 1993 were scrutinized both for clinical and pathological data. Death occurred followed several days of

combination of alcohol-related hypoglycaemia and ketoacidosis may be common.

threatening hypoglycemia.

**5. ALD and hypoglycemia** 

impairment in lipid metabolism.

Ischemic hepatitis also known Hypoxic hepatitis or shock liver, can be characterized by necrosis of the zone 3 hepatocytes and significant increase in serum aminotransferase levels. It is the consequence of multiorgan injury. Outcome is influenced by the severity of liver impairment and the etiology and severity of the basic disease (Fuhrmann, V et al., 2009).The syndrome occurs under conditions of clinical setting of cardiac, circulatory or respiratory failure. It is recognized as the most frequent cause of acute liver injury with a reported prevalence of up to 10% in the intensive care unit (Fuhrmann, V et al., 2010). Patients with ischemic hepatitis and vasopressor therapy have a significantly increased mortality risk in the medical intensive care unit population. Ischemic hepatitis causes several complications including spontaneous hypoglycemia which can be considered secondary to impairment of gluconeogenic response in the exhausted liver (Fuhrmann, V et al., 2010; Fuhrmann, V et al., 2009; Nomura, T et al., 2009).

### **7. Sepsis**

#### **7.1 Introduction**

Definition "Systemic Inflammatory Response Syndrome or **(SIRS)** is evidence of the body's ongoing inflammatory response. When SIRS is suspected or known to be caused by an infection, this is sepsis. Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing, coagulation or other blood abnormalities, decreased urine production, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis), this is septic shock. Sepsis can lead to multiple organ dysfunction syndrome (MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among other things.

Sepsis can be defined as the body's response to an infection. An infection is caused by microorganisms or bacteria invading the body and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis is acquired quickest with infections developed in surgery and physical contact with someone with sepsis.

Bacteremia is the presence of viable bacteria in the bloodstream. Likewise, the terms viremia and fungemia simply refer to viruses and fungi in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental

Inflammation and Hypoglycemia: The Lipid Connection 105

patients with and without diabetes. In elderly hospitalized patients a predicted increase inhospital 3- and 6-month cumulative mortality has been documented (Kagansky, N et al., 2003). In addition, sepsis is 10 times more common in these patients than in nonhypoglycemic patients. Previously, it has been shown that features of hepatitis and steatosis are the primary histological findings in the liver of patients dying from sepsis (Koskinas, J et al., 2008). The hypoglycemic effect due to fatty liver is also a known phenomenon in alcoholic patients and is related to the fatty liver sudden death syndrome (Denmark, LN, 1993; Randall, B, 1980; Yuzuriha, T et al., 1997). Altogether, the accumulated data suggest that although fatty liver and inflammation can generate a phenotype of insulin resistance, it can also lead to severe hypoglycemic life-threatening situations in patients with steatosis and acute inflammation due to an increase in hepatic insulin sensitivity (Thompson, BT, 2008; van der Crabben, SN et al., 2009). The mechanism(s) for hypoglycemia with sepsis is not well defined. Depleted glycogen stores, impaired gluconeogenesis and increased peripheral glucose utilization may all be contributing factors. Incubation of bacteria in fresh blood at room temperature does not increase the normal rate of breakdown of glucose suggesting that the hypoglycemia occurs in vivo by increased glucose utilization or by a decrease in glucose production. Hypoglycemia is an important sign of overwhelming sepsis (Miller, SI et al., 1980). Fischer et al" have reported that hypoglycemic episodes in nondiabetics were associated with infection and septic shock. The majority of cases of hypoglycemia reported in their study were related to liver disease, infections, shock, pregnancy, neoplasia, or burns. Hypoglycemia was not the apparent cause of death in any patient, but the overall hospital mortality was 27 percent and was related to the degree of hypoglycemia and the number of risk factors for hypoglycemia (Fischer, KF et al., 1986). In 1991 Charles et al have studied the mechanism by which infection can lead to hypoglycemia. A hypermetabolic septic state was produced in rats by subcutaneous injections of live Escherichia coli. Sepsis increased whole body glucose disposal by 53% under basal euglycemic conditions and this increase resulted from an enhanced rate of glucose removal by liver, spleen, lung, ileum, and skin. In sepsis, the rate of non-insulinmediated glucose uptake (NIMGU) was46% higher than in nonseptic animals. Severe hypoglycemia (2 mmol/L) produced a relative insulin deficiency and decreased whole body glucose disposal in both septic and nonseptic animals by 53% to 56%. Compared with euglycemic insulinopenic animals. The decrease in blood glucose decreased glucose uptake by all tissues examined, except brain and heart. However, sepsis still increased glucose uptake by liver, spleen, lung, ileum, and skin (25% to SO%), compared with hypoglycemic nonseptic rats. Therefore, the conclusion of the study was that sepsis increases NIMGU under basal conditions due to an increased glucose uptake by macrophage-rich tissues, and that this enhanced rate is maintained during hypoglycemia (Lang, CH & C Dobrescu, 1991). It is therefore suggested that during sepsis there is increased glucose utilization by macrophages-rich tissues, which may lead to hypoglycemia. However, there is also a strong connection between the liver capacity to generate glucose and the development of hypoglycemia. A case report which connect hypoglycemia with sepsis and liver disease was reported at 1994 in Japan. A 78-year-old woman that was admitted to a hospital because of disturbance of consciousness. On admission, the body temperature was 35.5 degrees C and systolic blood pressure was 50 mmHg. Ascites and semicomatose consciousness were detected. Laboratory evaluation demonstrated the following values: leukocyte count 38800/microliters, blood sugar 3 mg/l and arterial blood pH 6.9. Therapy with

procedures can cause bacterial infection of the heart valves (known as endocarditis) in highrisk patients. Conversely, a systemic inflammatory response syndrome can occur in patients without the presence of infection, for example in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis" (wikipedia).

Severe sepsis is a significant cause of mortality worldwide. Current research estimates that more than 9% of all deaths in the US can be attributed to severe sepsis. Experimental evidence shows that the liver is an important target organ in the development of multiple organ dysfunction during sepsis (Koo, DJ et al., 1999; Koo, DJ et al., 2000). Due to its major role in metabolism and host-defense mechanisms, the liver is pivotal in participating in the systemic response to severe infection, because it contains the largest mass of resident macrophage Kupffer cells (KC) in the body, making up approximately 15% of the liver cells (Szabo, G et al., 2002). KC are highly relevant in the inflammatory response to bacterial infection and non-bacterial inflammation by 1) playing a major role in both clearance and detoxification, e.g. removal of LPS from the circulation (especially the portal vein) and 2) producing inflammatory mediators (Van Amersfoort, ES et al., 2003).

### **8. Sepsis and hypoglycemia**

#### **8.1 The use of intensive insulin therapy (IIT) to maintain normal blood glucose levels in septic patients**

At 2001 van den Berghe and colleagues published the clinical implications of tight euglycemic control (van den Berghe, G et al., 2001). This observation significantly and rapidly changed intensive care unit (ICU) practice. It has been suggested that insulin administered to maintain glucose at levels below 110 mg/dl decreased mortality, the incidence of infections, sepsis, and sepsis-associated multiorgan failure in surgical patients, reduced kidney injury, and accelerated weaning from mechanical ventilation and discharge from the ICU in medical patients. However, current evidences suggest that the tight euglycemic control which is implemented in intensive care units around the world could be detrimental. Increasing evidence suggest that tight euglycemic control is which is associated with development of hypoglycemia has detrimental outcomes (Brunkhorst, FM et al., 2008; Jeschke, MG et al., 2010).Therefore, In practice regulating blood glucose levels is recommended to target glucose level below 8.3 mmol/L. This is indicated for the management of severe sepsis by the Surviving Sepsis guidelines (Orford, NR, 2006)

The main problem with IIT is the risk of development of hypoglycemia. The recent trials reporting reduced morbidity and mortality in critically ill patients treated with IIT require careful examination, including the subsequent post-hoc analyses. An understanding of the molecular and metabolic mechanisms by which IIT may be beneficial and the evidence that it benefits patients with severe sepsis, and a review of the risks of hypoglycaemia are also necessary when deciding whether to implement IIT in severe sepsis. Patients with severe sepsis are likely to benefit from IIT based on metabolic effects and their prolonged stays in the intensive care unit. All together, The current evidence suggests IIT should be implemented, aiming for the lowest glycaemic range that can be safely achieved while avoiding hypoglycaemia.

#### **8.2 Development of hypoglycemia in septic patients without IIT**

The severity of sepsis is shown to correlate with the risk of sustaining hyperglycemia as well as critical hypoglycemia (Krinsley, JS, 2008). Hypoglycemia during hospitalization occurs in

procedures can cause bacterial infection of the heart valves (known as endocarditis) in highrisk patients. Conversely, a systemic inflammatory response syndrome can occur in patients without the presence of infection, for example in those with burns, polytrauma, or the initial

Severe sepsis is a significant cause of mortality worldwide. Current research estimates that more than 9% of all deaths in the US can be attributed to severe sepsis. Experimental evidence shows that the liver is an important target organ in the development of multiple organ dysfunction during sepsis (Koo, DJ et al., 1999; Koo, DJ et al., 2000). Due to its major role in metabolism and host-defense mechanisms, the liver is pivotal in participating in the systemic response to severe infection, because it contains the largest mass of resident macrophage Kupffer cells (KC) in the body, making up approximately 15% of the liver cells (Szabo, G et al., 2002). KC are highly relevant in the inflammatory response to bacterial infection and non-bacterial inflammation by 1) playing a major role in both clearance and detoxification, e.g. removal of LPS from the circulation (especially the portal vein) and 2)

**8.1 The use of intensive insulin therapy (IIT) to maintain normal blood glucose levels** 

At 2001 van den Berghe and colleagues published the clinical implications of tight euglycemic control (van den Berghe, G et al., 2001). This observation significantly and rapidly changed intensive care unit (ICU) practice. It has been suggested that insulin administered to maintain glucose at levels below 110 mg/dl decreased mortality, the incidence of infections, sepsis, and sepsis-associated multiorgan failure in surgical patients, reduced kidney injury, and accelerated weaning from mechanical ventilation and discharge from the ICU in medical patients. However, current evidences suggest that the tight euglycemic control which is implemented in intensive care units around the world could be detrimental. Increasing evidence suggest that tight euglycemic control is which is associated with development of hypoglycemia has detrimental outcomes (Brunkhorst, FM et al., 2008; Jeschke, MG et al., 2010).Therefore, In practice regulating blood glucose levels is recommended to target glucose level below 8.3 mmol/L. This is indicated for the

management of severe sepsis by the Surviving Sepsis guidelines (Orford, NR, 2006)

**8.2 Development of hypoglycemia in septic patients without IIT** 

The main problem with IIT is the risk of development of hypoglycemia. The recent trials reporting reduced morbidity and mortality in critically ill patients treated with IIT require careful examination, including the subsequent post-hoc analyses. An understanding of the molecular and metabolic mechanisms by which IIT may be beneficial and the evidence that it benefits patients with severe sepsis, and a review of the risks of hypoglycaemia are also necessary when deciding whether to implement IIT in severe sepsis. Patients with severe sepsis are likely to benefit from IIT based on metabolic effects and their prolonged stays in the intensive care unit. All together, The current evidence suggests IIT should be implemented, aiming for the lowest glycaemic range that can be safely achieved while

The severity of sepsis is shown to correlate with the risk of sustaining hyperglycemia as well as critical hypoglycemia (Krinsley, JS, 2008). Hypoglycemia during hospitalization occurs in

state in pancreatitis and chemical pneumonitis" (wikipedia).

producing inflammatory mediators (Van Amersfoort, ES et al., 2003).

**8. Sepsis and hypoglycemia** 

**in septic patients** 

avoiding hypoglycaemia.

patients with and without diabetes. In elderly hospitalized patients a predicted increase inhospital 3- and 6-month cumulative mortality has been documented (Kagansky, N et al., 2003). In addition, sepsis is 10 times more common in these patients than in nonhypoglycemic patients. Previously, it has been shown that features of hepatitis and steatosis are the primary histological findings in the liver of patients dying from sepsis (Koskinas, J et al., 2008). The hypoglycemic effect due to fatty liver is also a known phenomenon in alcoholic patients and is related to the fatty liver sudden death syndrome (Denmark, LN, 1993; Randall, B, 1980; Yuzuriha, T et al., 1997). Altogether, the accumulated data suggest that although fatty liver and inflammation can generate a phenotype of insulin resistance, it can also lead to severe hypoglycemic life-threatening situations in patients with steatosis and acute inflammation due to an increase in hepatic insulin sensitivity (Thompson, BT, 2008; van der Crabben, SN et al., 2009). The mechanism(s) for hypoglycemia with sepsis is not well defined. Depleted glycogen stores, impaired gluconeogenesis and increased peripheral glucose utilization may all be contributing factors. Incubation of bacteria in fresh blood at room temperature does not increase the normal rate of breakdown of glucose suggesting that the hypoglycemia occurs in vivo by increased glucose utilization or by a decrease in glucose production. Hypoglycemia is an important sign of overwhelming sepsis (Miller, SI et al., 1980). Fischer et al" have reported that hypoglycemic episodes in nondiabetics were associated with infection and septic shock. The majority of cases of hypoglycemia reported in their study were related to liver disease, infections, shock, pregnancy, neoplasia, or burns. Hypoglycemia was not the apparent cause of death in any patient, but the overall hospital mortality was 27 percent and was related to the degree of hypoglycemia and the number of risk factors for hypoglycemia (Fischer, KF et al., 1986). In 1991 Charles et al have studied the mechanism by which infection can lead to hypoglycemia. A hypermetabolic septic state was produced in rats by subcutaneous injections of live Escherichia coli. Sepsis increased whole body glucose disposal by 53% under basal euglycemic conditions and this increase resulted from an enhanced rate of glucose removal by liver, spleen, lung, ileum, and skin. In sepsis, the rate of non-insulinmediated glucose uptake (NIMGU) was46% higher than in nonseptic animals. Severe hypoglycemia (2 mmol/L) produced a relative insulin deficiency and decreased whole body glucose disposal in both septic and nonseptic animals by 53% to 56%. Compared with euglycemic insulinopenic animals. The decrease in blood glucose decreased glucose uptake by all tissues examined, except brain and heart. However, sepsis still increased glucose uptake by liver, spleen, lung, ileum, and skin (25% to SO%), compared with hypoglycemic nonseptic rats. Therefore, the conclusion of the study was that sepsis increases NIMGU under basal conditions due to an increased glucose uptake by macrophage-rich tissues, and that this enhanced rate is maintained during hypoglycemia (Lang, CH & C Dobrescu, 1991).

It is therefore suggested that during sepsis there is increased glucose utilization by macrophages-rich tissues, which may lead to hypoglycemia. However, there is also a strong connection between the liver capacity to generate glucose and the development of hypoglycemia. A case report which connect hypoglycemia with sepsis and liver disease was reported at 1994 in Japan. A 78-year-old woman that was admitted to a hospital because of disturbance of consciousness. On admission, the body temperature was 35.5 degrees C and systolic blood pressure was 50 mmHg. Ascites and semicomatose consciousness were detected. Laboratory evaluation demonstrated the following values: leukocyte count 38800/microliters, blood sugar 3 mg/l and arterial blood pH 6.9. Therapy with

Inflammation and Hypoglycemia: The Lipid Connection 107

Fig. 6. **Fat accumulation in FaO cultures.** FaO cells were cultured and exposed to FAs mixture (2:1 oleate/palmitate with 1% BSA) at different concentrations for 18 hours (A) or to

final concentration of 1mM FAs for different times (B). Alternatively, FaO cells were cultured and exposed to FAs mixture (2:1 oleate/palmitate with 1% BSA) or to FAs-Br mixture (2:1 oleate/2-Bromopalmitate with 1% BSA) to final concentration of 1mM FAs (C). After that, cells were stained with Nile-Red and fluorescence was examined by FACS

analysis. Means with different letters differ at P<0.05.

catecholamine and antibiotics was started, but she expired 10 hours after admission. Bacteroides ovatus was detected from her blood. Autopsy findings disclosed the connection to advance liver disease and indicated abscess and perforation of the uterus, and liver cirrhosis (Suzuki, A et al., 1994). It is known that Sepsis suppresses fatty acid oxidation, It has been reported that fatty acid oxidation is significantly suppressed under conditions of sepsis and endotoxemia. During the acute-phase response, fatty acid oxidation decrease is associated with hypertriglyceridemia. LPS was demonstrated to suppress FFAs oxidation, and consequently contributes to elevated plasma levels of FFAs and TGs. LPS suppresses FFAs oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues. LPS has been shown to selectively suppress the levels of PPARalpha and PGC-1alpha in tissues (Maitra, U et al., 2009). The decrease was rapid and occurred at very low doses of LPS. Similar decreases in levels of these genes occurred during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1alpha, and medium chain acyl coA dehydrogenase pathway is a general response during infection and inflammation (Kim, MS et al., 2005). We have demonstrated in a model of liver steatosis and endotoxemia that the expression of gluconeogenic enzymes and gluconeogenesis are strongly suppressed. This was accompanied with lowered blood glucose levels. The treated mice had a phenotype of insulin sensitivity with decreased blood insulin levels (Tirosh, O et al., 2010). Therefore, the effect of free fatty acids and triglycerids on expression of key gluconeogenic enzymes was studied. The effect of exposing hepatocytes to free fatty acids was to suppress the inducible expression of gluconeogenic enzymes Figure 5 and Figure 6.

catecholamine and antibiotics was started, but she expired 10 hours after admission. Bacteroides ovatus was detected from her blood. Autopsy findings disclosed the connection to advance liver disease and indicated abscess and perforation of the uterus, and liver cirrhosis (Suzuki, A et al., 1994). It is known that Sepsis suppresses fatty acid oxidation, It has been reported that fatty acid oxidation is significantly suppressed under conditions of sepsis and endotoxemia. During the acute-phase response, fatty acid oxidation decrease is associated with hypertriglyceridemia. LPS was demonstrated to suppress FFAs oxidation, and consequently contributes to elevated plasma levels of FFAs and TGs. LPS suppresses FFAs oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues. LPS has been shown to selectively suppress the levels of PPARalpha and PGC-1alpha in tissues (Maitra, U et al., 2009). The decrease was rapid and occurred at very low doses of LPS. Similar decreases in levels of these genes occurred during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1alpha, and medium chain acyl coA dehydrogenase pathway is a general response during infection and inflammation (Kim, MS et al., 2005). We have demonstrated in a model of liver steatosis and endotoxemia that the expression of gluconeogenic enzymes and gluconeogenesis are strongly suppressed. This was accompanied with lowered blood glucose levels. The treated mice had a phenotype of insulin sensitivity with decreased blood insulin levels (Tirosh, O et al., 2010). Therefore, the effect of free fatty acids and triglycerids on expression of key gluconeogenic enzymes was studied. The effect of exposing hepatocytes to free fatty acids was to suppress the inducible

expression of gluconeogenic enzymes Figure 5 and Figure 6.

**PEPCK expression**

letters differ at P<0.05.

**(fold change)**

**dexamethasone - + - + - + - + pre-treatment 1h FAs 18h FAs 18h FAs-Br**

Fig. 5. **Inhibition of gluconeogenic response by free FAs in FaO cells.** FaO cells were cultured and pre-treated with FAs mixture (2:1 oleate/palmitate with 1% BSA) or with FAs-Br mixture (2:1 oleate/2-Bromopalmitate with 1% BSA) to final concentration of 1mM FAs. After that, dexamethasone (1μM) was added to cells media for 6 hours. mRNA expression levels of PEPCK was measured by quantitative real-time RT-PCR. Means with different

**a a**

**c c c c**

**b b**

Fig. 6. **Fat accumulation in FaO cultures.** FaO cells were cultured and exposed to FAs mixture (2:1 oleate/palmitate with 1% BSA) at different concentrations for 18 hours (A) or to final concentration of 1mM FAs for different times (B). Alternatively, FaO cells were cultured and exposed to FAs mixture (2:1 oleate/palmitate with 1% BSA) or to FAs-Br mixture (2:1 oleate/2-Bromopalmitate with 1% BSA) to final concentration of 1mM FAs (C). After that, cells were stained with Nile-Red and fluorescence was examined by FACS analysis. Means with different letters differ at P<0.05.

Inflammation and Hypoglycemia: The Lipid Connection 109

following intensive blood infusion of triglycerides (TGs) in rats (Tirosh, O et al., 2009). Thus, it appears that NO can be both toxic or protective, depending on the acute physicological

In the case of sepsis, there are also contractory reports concerning the role of NO. Although it has been suggested that NO is a mediator of organ dysfunction, different opinions suggest a protective role of NO in sepsis. Indeed, numerous reports of benefits associated with NO donor administration in clinical and preclinical studies of sepsis have been published (Lamontagne, F et al., 2008). Obesity increases sensitivity to endotoxin liver injury. It is known that fatty liver sensitivity to acute inflammation injury is much higher compared to normal livers (Yang, SQ et al., 1997). Our published studies in a mouse model of fatty liver and endotoxemia demonstrated a significant protective role for iNOS expression. iNOS(-/-) mice were found to be more sensitive to liver damage thereby supporting the hypothesis that iNOS has a protective effect. Additionally, iNOS(-/-) mice with fatty liver suffered

from severe fatal hypoglycemia after endotoxic treatment (Tirosh, O et al., 2010).

**9.2 Hyperglycemia or hypoglycemia: A paradox of inflammation, and the involvement** 

Along with a rising prevalence of non-alcoholic fatty liver disease (NAFLD), there is a marked increase in individuals suffering from metabolic impairments. One widespread imbalance is the insulin resistance syndrome or metabolic syndrome which refers to a constellation of symptoms, including glucose intolerance, obesity, dyslipidemia, and hypertension. This syndrome is known to promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. The liver plays a major role in the regulation of glucose, lipid and energy metabolism, which are tightly regulated by insulin (Leclercq, IA et al., 2007; Raddatz, D & G Ramadori, 2007). In addition, insulin resistance is now recognized as a pathological factor in the development of NAFLD (Leclercq, IA et al., 2007; Raddatz, D & G Ramadori, 2007). It has been suggested that prolonged elevation of the levels of sterol regulatory element binding proteins (SREBPs) is responsible for inhibition of insulin signaling in fatty liver (Shimano, H, 2007) and that the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C(PKC ) with subsequent impairments in insulin signaling (Samuel, VT et al.). Hepatic insulin resistance can be defined as the failure of insulin to adequately suppress hepatic glucose production

Several studies indicate the involvement of inflammatory activation in the development of hepatic and peripheral insulin resistance (Cai, D et al., 2005). On the other hand, acute inflammation induced by lipopolysaccharides (LPS) facilitates a hypoglycemic effect and impairment of hepatic Glucose-6 phosphatase (G6Pase) expression (Lo, YC et al., 2004; Maitra, SR et al., 1999; Oguri, S et al., 2002). Indeed, as metioned above in critically ill patients, sepsis-induced hypoglycemia is a well known event (van der Crabben, SN et al., 2009). We showed by temporal kinetics that the rapid induction of iNOS played a role in counteracting hypoglycemic effect of LPS and lipids rather than exacerbating it (Tirosh, O et al.). NO had a direct stimulatory effect promoting liver glucose production, making iNOS expression necessary for survival. Experiments performed with the NO donor DETA-NONOate in cultured hepatocytes showed a positive effect of NO on expression of gluconeogenic enzymes. Our data indicate that NO generated by the iNOS protein can support the expression of PGC 1alpha and liver gluconeogenic genes during acute

environment in the liver.

**of nitric oxide** 

(Weickert, MO & AF Pfeiffer, 2006).

The mechanism for the development of hypoglycemia during sepsis and the lipid connection can be therefore explained by the following figure 7:

Fig. 7. LPS and bacteria facilitate 1 ) non-insulin-mediated glucose uptake 2) release of triglycerides and suppression of beta-oxidation in hepatocytes therefore elevating the FFA levels. This results in suppression of liver glucose output capacity. The results is hypoglycemia.

### **9. Nitric oxide as a potential antihypoglycemic agent**

### **9.1 Nitric oxide involvement in liver damage and sepsis**

One of the main effects of the inflammatory response in the liver is an increase in the levels of inducible nitric oxide synthase (iNOS). Therefore, it has been postulated that nitric oxide (NO) would contribute to hepatotoxicity through inhibition of ATP synthesis, increased reactive oxygen species (ROS), and the inability to adapt to hypoxic stress (Mantena, SK et al., 2008). Other studies imply that decreased production of NO from endothelial nitric oxide synthase (eNOS) contributes to liver pathology via dysregulation of blood flow and oxygen delivery (Liu, J & MP Waalkes, 2005). Furthermore, in iNOS knockout mice, hepatocytes undergo necrosis and apoptosis after PH, indicating that the production of NO is essential to protect hepatocytes from death after liver resection (Rai, RM et al., 1998). We have demonstrated that a decreased in eNOS expression precedes formation of liver damage

The mechanism for the development of hypoglycemia during sepsis and the lipid

Fig. 7. LPS and bacteria facilitate 1 ) non-insulin-mediated glucose uptake 2) release of triglycerides and suppression of beta-oxidation in hepatocytes therefore elevating the FFA

One of the main effects of the inflammatory response in the liver is an increase in the levels of inducible nitric oxide synthase (iNOS). Therefore, it has been postulated that nitric oxide (NO) would contribute to hepatotoxicity through inhibition of ATP synthesis, increased reactive oxygen species (ROS), and the inability to adapt to hypoxic stress (Mantena, SK et al., 2008). Other studies imply that decreased production of NO from endothelial nitric oxide synthase (eNOS) contributes to liver pathology via dysregulation of blood flow and oxygen delivery (Liu, J & MP Waalkes, 2005). Furthermore, in iNOS knockout mice, hepatocytes undergo necrosis and apoptosis after PH, indicating that the production of NO is essential to protect hepatocytes from death after liver resection (Rai, RM et al., 1998). We have demonstrated that a decreased in eNOS expression precedes formation of liver damage

levels. This results in suppression of liver glucose output capacity. The results is

**9. Nitric oxide as a potential antihypoglycemic agent 9.1 Nitric oxide involvement in liver damage and sepsis** 

hypoglycemia.

connection can be therefore explained by the following figure 7:

following intensive blood infusion of triglycerides (TGs) in rats (Tirosh, O et al., 2009). Thus, it appears that NO can be both toxic or protective, depending on the acute physicological environment in the liver.

In the case of sepsis, there are also contractory reports concerning the role of NO. Although it has been suggested that NO is a mediator of organ dysfunction, different opinions suggest a protective role of NO in sepsis. Indeed, numerous reports of benefits associated with NO donor administration in clinical and preclinical studies of sepsis have been published (Lamontagne, F et al., 2008). Obesity increases sensitivity to endotoxin liver injury. It is known that fatty liver sensitivity to acute inflammation injury is much higher compared to normal livers (Yang, SQ et al., 1997). Our published studies in a mouse model of fatty liver and endotoxemia demonstrated a significant protective role for iNOS expression. iNOS(-/-) mice were found to be more sensitive to liver damage thereby supporting the hypothesis that iNOS has a protective effect. Additionally, iNOS(-/-) mice with fatty liver suffered from severe fatal hypoglycemia after endotoxic treatment (Tirosh, O et al., 2010).

#### **9.2 Hyperglycemia or hypoglycemia: A paradox of inflammation, and the involvement of nitric oxide**

Along with a rising prevalence of non-alcoholic fatty liver disease (NAFLD), there is a marked increase in individuals suffering from metabolic impairments. One widespread imbalance is the insulin resistance syndrome or metabolic syndrome which refers to a constellation of symptoms, including glucose intolerance, obesity, dyslipidemia, and hypertension. This syndrome is known to promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. The liver plays a major role in the regulation of glucose, lipid and energy metabolism, which are tightly regulated by insulin (Leclercq, IA et al., 2007; Raddatz, D & G Ramadori, 2007). In addition, insulin resistance is now recognized as a pathological factor in the development of NAFLD (Leclercq, IA et al., 2007; Raddatz, D & G Ramadori, 2007). It has been suggested that prolonged elevation of the levels of sterol regulatory element binding proteins (SREBPs) is responsible for inhibition of insulin signaling in fatty liver (Shimano, H, 2007) and that the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C(PKC ) with subsequent impairments in insulin signaling (Samuel, VT et al.). Hepatic insulin resistance can be defined as the failure of insulin to adequately suppress hepatic glucose production (Weickert, MO & AF Pfeiffer, 2006).

Several studies indicate the involvement of inflammatory activation in the development of hepatic and peripheral insulin resistance (Cai, D et al., 2005). On the other hand, acute inflammation induced by lipopolysaccharides (LPS) facilitates a hypoglycemic effect and impairment of hepatic Glucose-6 phosphatase (G6Pase) expression (Lo, YC et al., 2004; Maitra, SR et al., 1999; Oguri, S et al., 2002). Indeed, as metioned above in critically ill patients, sepsis-induced hypoglycemia is a well known event (van der Crabben, SN et al., 2009). We showed by temporal kinetics that the rapid induction of iNOS played a role in counteracting hypoglycemic effect of LPS and lipids rather than exacerbating it (Tirosh, O et al.). NO had a direct stimulatory effect promoting liver glucose production, making iNOS expression necessary for survival. Experiments performed with the NO donor DETA-NONOate in cultured hepatocytes showed a positive effect of NO on expression of gluconeogenic enzymes. Our data indicate that NO generated by the iNOS protein can support the expression of PGC 1alpha and liver gluconeogenic genes during acute

Inflammation and Hypoglycemia: The Lipid Connection 111

Browning, J.D., Szczepaniak, L.S., Dobbins, R., Nuremberg, P., Horton, J.D., Cohen, J.C.,

population in the United States: impact of ethnicity. *Hepatology*. 40:1387-95. Brunkhorst, F.M., Engel, C., Bloos, F., Meier-Hellmann, A., Ragaller, M., Weiler, N., Moerer,

Cai, D., Yuan, M., Frantz, D.F., Melendez, P.A., Hansen, L., Lee, J., & Shoelson, S.E. 2005.

De Minicis, S., & Brenner, D.A. 2008. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. *J Gastroenterol Hepatol*. 23 Suppl 1:S98-103. Denk, H., Stumptner, C., Fuchsbichler, A., & Zatloukal, K. 2005. [Alcoholic and non-

Denmark, L.N. 1993. The investigation of beta-hydroxybutyrate as a marker for sudden

Farrell, G.C., Teoh, N.C., & McCuskey, R.S. 2008. Hepatic microcirculation in fatty liver

Fischer, K.F., Lees, J.A., & Newman, J.H. 1986. Hypoglycemia in hospitalized patients.

Fuhrmann, V., Jager, B., Zubkova, A., & Drolz, A. 2010. Hypoxic hepatitis - epidemiology, pathophysiology and clinical management. *Wien Klin Wochenschr*. 122:129-39. Fuhrmann, V., Kneidinger, N., Herkner, H., Heinz, G., Nikfardjam, M., Bojic, A.,

factors for mortality in critically ill patients. *Intensive Care Med*. 35:1397-405. Gordon, G.G., & Lieber, C.S. 1992. Alcohol, hormones, and metabolism. New York: Plenum

Hasse, J., & Matarese, L. 2004. Medical nutrition therapy for liver, biliary system, and

Hickman, I., Russell, A., Prins, J., Macdonald, G., & 2008. Should patient with type 2

Hirschey, M.D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D.B., Grueter,

Houten, S.M., & Wanders, R.J. 2010. A general introduction to the biochemistry of

mitochondrial fatty acid beta-oxidation. *J Inherit Metab Dis*.

exocrine pancreas disorders. Elsevier, Philadelphia, . 738-67 pp.

Schellongowski, P., Angermayr, B., Kitzberger, R., Warszawska, J., Holzinger, U., Schenk, P., & Madl, C. 2009. Hypoxic hepatitis: underlying conditions and risk

diabetes and raised liver enzymes be referred for further evaluation of liver disease? Diabetes. *In* Res and Clin Prac [serial online]. Vol. .Available at

C.A., Harris, C., Biddinger, S., Ilkayeva, O.R., Stevens, R.D., Li, Y., Saha, A.K., Ruderman, N.B., Bain, J.R., Newgard, C.B., Farese, R.V., Jr., Alt, F.W., Kahn, C.R., & Verdin, E. 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible

death due to hypoglycemia in alcoholics. *Forensic Sci Int*. 62:225-32.

pentastarch resuscitation in severe sepsis. *N Engl J Med*. 358:125-39.

alcoholic steatohepatitis]. *Verh Dtsch Ges Pathol*. 89:137-43.

and NF-kappaB. *Nat Med*. 11:183-90.

disease. *Anat Rec (Hoboken)*. 291:684-92.

Publishing Corp. 55-90 pp.

www.sciencedirect.com . ;80:e10-e12.

enzyme deacetylation. *Nature*. 464:121-5.

Causes and outcomes. *N Engl J Med*. 315:1245-50.

Grundy, S.M., & Hobbs, H.H. 2004. Prevalence of hepatic steatosis in an urban

O., Gruendling, M., Oppert, M., Grond, S., Olthoff, D., Jaschinski, U., John, S., Rossaint, R., Welte, T., Schaefer, M., Kern, P., Kuhnt, E., Kiehntopf, M., Hartog, C., Natanson, C., Loeffler, M., & Reinhart, K. 2008. Intensive insulin therapy and

Local and systemic insulin resistance resulting from hepatic activation of IKK-beta

inflammation. We believe that this effect is mediated by NO's capacity to promote the removal of free fatty acids (FFAs). Indeed, NO was found to act as a signaling molecule that can activate the transcription factor co-activator PGC 1alpha facilitating mitochondrial biogenesis (Nisoli, E & MO Carruba, 2006; Nisoli, E et al., 2007).

Our results that nitric oxide produced during the acute inflammatory process in fatty liver promotes PGC1 expression and liver glucose production supports the hypothesis that it acts as an antihypoglycemic factor. The lipotoxicity during acute inflammation in the fatty liver is manifested by increased oxidative stress and lipid peroxidation and therefore NO also function as an antioxidant (Kanner, J et al., 1991; Kanner, J et al., 1992; Volk, J et al., 2009) protecting the liver. Therefore, NO derived from inducible nitric oxide synthase (iNOS) may paradoxically function as an antioxidant protecting fatty liver during acute inflammation. This phenomenon is probably quite the reverse of the reactive nitrogen species and ROS effect in long term chronic inflammation which leads to liver cirrhosis (Wei, CL et al., 2005).

### **10. Acknowledgment**

I would like to thank My Ph.D. Student Noga Budick-Harmelin for performing the experiments with FaO hepatocytes treated with fatty acid mix (Fig. 5 and 6). I thank also my student khem Bahadur Adhikari for his writing help.

### **11. References**


inflammation. We believe that this effect is mediated by NO's capacity to promote the removal of free fatty acids (FFAs). Indeed, NO was found to act as a signaling molecule that can activate the transcription factor co-activator PGC 1alpha facilitating mitochondrial

Our results that nitric oxide produced during the acute inflammatory process in fatty liver promotes PGC1 expression and liver glucose production supports the hypothesis that it acts as an antihypoglycemic factor. The lipotoxicity during acute inflammation in the fatty liver is manifested by increased oxidative stress and lipid peroxidation and therefore NO also function as an antioxidant (Kanner, J et al., 1991; Kanner, J et al., 1992; Volk, J et al., 2009) protecting the liver. Therefore, NO derived from inducible nitric oxide synthase (iNOS) may paradoxically function as an antioxidant protecting fatty liver during acute inflammation. This phenomenon is probably quite the reverse of the reactive nitrogen species and ROS effect in long term chronic inflammation which leads to liver cirrhosis (Wei, CL et al., 2005).

I would like to thank My Ph.D. Student Noga Budick-Harmelin for performing the experiments with FaO hepatocytes treated with fatty acid mix (Fig. 5 and 6). I thank also my

Adachi, M., & Brenner, D.A. 2005. Clinical syndromes of alcoholic liver disease. *Dig Dis*.

Adams, L.A., & Lindor, K.D. 2007. Nonalcoholic fatty liver disease. *Ann Epidemiol*. 17:863-9. Albano, E. 2008. Oxidative mechanisms in the pathogenesis of alcoholic liver disease. *Mol* 

Alkhouri, N., Dixon, L.J., & Feldstein, A.E. 2009. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. *Expert Rev Gastroenterol Hepatol*. 3:445-51. Amarapurkar, D., Kamani, P., Patel, N., Gupte, P., Kumar, P., Agal, S., Baijal, R., Lala, S.,

Angulo, P., & Lindor, K.D. 2002. Non-alcoholic fatty liver disease. *J Gastroenterol Hepatol*. 17

Arky, R.A., & Freinkel, N. 1966. Alcohol hypoglycemia. V. Alcohol infusion to test

Baruteau, J., Levade, T., Redonnet-Vernhet, I., Mesli, S., Bloom, M.C., & Broue, P. 2009.

Barve, A., Khan, R., Marsano, L., Ravindra, K.V., & McClain, C. 2008. Treatment of alcoholic

Bergheim, I., McClain, C.J., & Arteel, G.E. 2005. Treatment of alcoholic liver disease. *Dig Dis*.

disease: population based study. *Ann Hepatol*. 6:161-3.

Angulo, P. 2007. Obesity and nonalcoholic fatty liver disease. *Nutr Rev*. 65:S57-63.

Chaudhary, D., & Deshpande, A. 2007. Prevalence of non-alcoholic fatty liver

gluconeogenesis in starvation, with special reference to obesity. *N Engl J Med*.

Hypoketotic hypoglycemia with myolysis and hypoparathyroidism: an unusual association in medium chain acyl-CoA desydrogenase deficiency (MCADD). *J* 

biogenesis (Nisoli, E & MO Carruba, 2006; Nisoli, E et al., 2007).

student khem Bahadur Adhikari for his writing help.

*Pediatr Endocrinol Metab*. 22:1175-7.

liver disease. *Ann Hepatol*. 7:5-15.

**10. Acknowledgment** 

23:255-63.

*Aspects Med*. 29:9-16.

Suppl:S186-90.

274:426-33.

23:275-84.

**11. References** 


Inflammation and Hypoglycemia: The Lipid Connection 113

Lim, J.H., Lee, J.C., Lee, Y.H., Choi, I.Y., Oh, Y.K., Kim, H.S., Park, J.S., & Kim, W.K. 2006.

Listenberger, L.L., Han, X., Lewis, S.E., Cases, S., Farese, R.V., Jr., Ory, D.S., & Schaffer, J.E.

Liu, J., & Waalkes, M.P. 2005. Nitric oxide and chemically induced hepatotoxicity: beneficial

Lo, Y.C., Wang, C.C., Shen, K.P., Wu, B.N., Yu, K.L., & Chen, I.J. 2004. Urgosedin inhibits

Ludwig, J., Viggiano, T.R., McGill, D.B., & Oh, B.J. 1980. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. *Mayo Clin Proc*. 55:434-8. Lumeng, L., & Crabb, D.W. 2001. Alcoholic liver disease. *Curr Opin Gastroenterol*. 17:211-20.

Maitra, S.R., Gestring, M.L., El-Maghrabi, M.R., Lang, C.H., & Henry, M.C. 1999. Endotoxin-

Maitra, U., Chang, S., Singh, N., & Li, L. 2009. Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia. *Mol Immunol*. 47:420-5. Mantena, S.K., King, A.L., Andringa, K.K., Eccleston, H.B., & Bailey, S.M. 2008.

Miller, S.I., Wallace, R.J., Jr., Musher, D.M., Septimus, E.J., Kohl, S., & Baughn, R.E. 1980.

Musso, G., Gambino, R., & Cassader, M. 2009. Non-alcoholic fatty liver disease from

Musso, G., Gambino, R., & Cassader, M. 2010. Non-alcoholic fatty liver disease from

Nisoli, E., & Carruba, M.O. 2006. Nitric oxide and mitochondrial biogenesis. *J Cell Sci*.

Nisoli, E., Clementi, E., Carruba, M.O., & Moncada, S. 2007. Defective mitochondrial

Nomura, T., Keira, N., Urakabe, Y., Naito, D., Nakayama, M., Kido, A., Kanemasa, H.,

O'Keefe, S.J., & Marks, V. 1977. Lunchtime gin and tonic a cause of reactive hypoglycaemia.

ischemic hepatitis manifesting as hypoglycemic attack. *Circ J*. 73:183-6. Novitskiy, G., Traore, K., Wang, L., Trush, M.A., & Mezey, E. 2006. Effects of ethanol and

biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome?

Matsubara, H., & Tatsumi, T. 2009. Chronic pericardial constriction induced severe

acetaldehyde on reactive oxygen species production in rat hepatic stellate cells.

obesity-induced fatty liver diseases. *Free Radic Biol Med*. 44:1259-72.

Hypoglycemia as a manifestation of sepsis. *Am J Med*. 68:649-54.

pathogenesis to management: an update. *Obes Rev*. 11:430-45.

pathogenesis to management: an update. *Obes Rev*.

nonenal. *J Neurochem*. 97:140-50.

*Mol Cell Biochem*. 196:79-83.

119:2855-62.

*Circ Res*. 100:795-806.

*Lancet*. 1:1286-8.

*Alcohol Clin Exp Res*. 30:1429-35.

97.

*Proc Natl Acad Sci U S A*. 100:3077-82.

lipopolysaccharide. *J Cardiovasc Pharmacol*. 44:363-71.

Madison, L.L. 1968. Ethanol-induced hypoglycemia. *Adv Metab Disord*. 3:85-109.

Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2E-

2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity.

effects of the liver-selective nitric oxide donor, V-PYRRO/NO. *Toxicology*. 208:289-

hypotension, hypoglycemia, and pro-inflammatory mediators induced by

induced alterations in hepatic glucose-6-phosphatase activity and gene expression.

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and


Imhof, A., Kratzer, W., Boehm, B., Meitinger, K., Trischler, G., Steinbach, G., Piechotowski,

overweight adolescents in the general population. *Eur J Epidemiol*. 22:889-97. Jeschke, M.G., Kraft, R., Emdad, F., Kulp, G.A., Williams, F.N., & Herndon, D.N. 2010.

Jimba, S., Nakagami, T., Takahashi, M., Wakamatsu, T., Hirota, Y., Iwamoto, Y., & Wasada,

Judith Fradkin, M.D. 1994. Alcohol Alert. Vol. (National Institute on Alcohol Abuse and

Kagansky, N., Levy, S., Rimon, E., Cojocaru, L., Fridman, A., Ozer, Z., & Knobler, H. 2003.

Kanner, J., Harel, S., & Granit, R. 1991. Nitric oxide as an antioxidant. *Arch Biochem Biophys*.

Kanner, J., Harel, S., & Granit, R. 1992. Nitric oxide, an inhibitor of lipid oxidation by

Kim, M.S., Shigenaga, J.K., Moser, A.H., Feingold, K.R., & Grunfeld, C. 2005. Suppression of

Kompare, M., & Rizzo, W.B. 2008. Mitochondrial fatty-acid oxidation disorders. *Semin* 

Koo, D.J., Chaudry, I.H., & Wang, P. 1999. Kupffer cells are responsible for producing

Koo, D.J., Chaudry, I.H., & Wang, P. 2000. Mechanism of hepatocellular dysfunction during sepsis: the role of gut-derived norepinephrine (review). *Int J Mol Med*. 5:457-65. Koskinas, J., Gomatos, I.P., Tiniakos, D.G., Memos, N., Boutsikou, M., Garatzioti, A.,

from sepsis: a clinico-pathological study. *World J Gastroenterol*. 14:1389-93. Krinsley, J.S. 2008. The severity of sepsis: yet another factor influencing glycemic control.

Lamontagne, F., Meade, M., Ondiveeran, H.K., Lesur, O., & Robichaud, A.E. 2008. Nitric

Lang, C.H., & Dobrescu, C. 1991. Sepsis-induced increases in glucose uptake by macrophage-rich tissues persist during hypoglycemia. *Metabolism*. 40:585-93. Leclercq, I.A., Da Silva Morais, A., Schroyen, B., Van Hul, N., & Geerts, A. 2007. Insulin

Lieber, C.S. 1997. Ethanol metabolism, cirrhosis and alcoholism. *Clin Chim Acta*. 257:59-84.

lipoxygenase, cyclooxygenase and hemoglobin. *Lipids*. 27:46-9.

dehydrogenase in the acute-phase response. *J Lipid Res*. 46:2282-8.

impaired glucose metabolism in Japanese adults. *Diabet Med*. 22:1141-5. Joy, D., Thava, V.R., & Scott, B.B. 2003. Diagnosis of fatty liver disease: is biopsy necessary?

should be the target? *Ann Surg*. 252:521-7; discussion 527-8.

*Eur J Gastroenterol Hepatol*. 15:539-43.

*Intern Med*. 163:1825-9.

*Pediatr Neurol*. 15:140-9.

*Res*. 83:151-7.

*Crit Care*. 12:194.

*Shock*. 30:653-9.

consequences>. *J Hepatol*. 47:142-56.

289:130-6.

Alcoholism Health, N.I.o.A.A.a.A.o.t.N.I.o., editor.

I., & Koenig, W. 2007. Prevalence of non-alcoholic fatty liver and characteristics in

Glucose control in severely thermally injured pediatric patients: what glucose range

T. 2005. Prevalence of non-alcoholic fatty liver disease and its association with

Hypoglycemia as a predictor of mortality in hospitalized elderly patients. *Arch* 

estrogen-related receptor alpha and medium-chain acyl-coenzyme A

inflammatory cytokines and hepatocellular dysfunction during early sepsis. *J Surg* 

Archimandritis, A., & Betrosian, A. 2008. Liver histology in ICU patients dying

oxide donors in sepsis: a systematic review of clinical and in vivo preclinical data.

resistance in hepatocytes and sinusoidal liver cells: Mechanisms and


Inflammation and Hypoglycemia: The Lipid Connection 115

Tirosh, O., Ilan, E., Budick-harmelin, N., Ramadori, G., & Madar, Z. 2009. Down regulation of eNOS in a nutritional model of fatty liver. *e-SPEN*. 4(2):e101-e104. Unger, R.H. 1995. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic

Van Amersfoort, E.S., Van Berkel, T.J., & Kuiper, J. 2003. Receptors, mediators, and

van den Berghe, G., Wouters, P., Weekers, F., Verwaest, C., Bruyninckx, F., Schetz, M.,

van der Crabben, S.N., Blumer, R.M., Stegenga, M.E., Ackermans, M.T., Endert, E., Tanck,

Vidali, M., Stewart, S.F., & Albano, E. 2008. Interplay between oxidative stress and

Volk, J., Gorelik, S., Granit, R., Kohen, R., & Kanner, J. 2009. The dual function of nitrite

Wei, C.L., Hon, W.M., Lee, K.H., & Khoo, H.E. 2005. Temporal expression of hepatic inducible nitric oxide synthase in liver cirrhosis. *World J Gastroenterol*. 11:362-7. Weickert, M.O., & Pfeiffer, A.F. 2006. Signalling mechanisms linking hepatic glucose and

Yan, E., Durazo, F., Tong, M., & Hong, K. 2007. Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management. *Nutr Rev*. 65:376-84. Yang, L., & Diehl, A. 2007. Role of immune response in nonalcoholic fatty liver disease: evidence in human and animal studies. Totowa: Humana Press. 337-45 pp. Yang, S.Q., Lin, H.Z., Lane, M.D., Clemens, M., & Diehl, A.M. 1997. Obesity increases

Yang, S.Q., Lin, H.Z., Mandal, A.K., Huang, J., & Diehl, A.M. 2001. Disrupted signaling and

Yuzuriha, T., Okudaira, M., Tominaga, I., Hori, S., Suzuki, H., Matsuo, Y., Shoji, M.,

Zelber-Sagi, S., Nitzan-Kaluski, D., Halpern, Z., & Oren, R. 2006. Prevalence of primary non-

therapy in the critically ill patients. *N Engl J Med*. 345:1359-67.

mechanisms involved in bacterial sepsis and septic shock. *Clin Microbiol Rev*.

Vlasselaers, D., Ferdinande, P., Lauwers, P., & Bouillon, R. 2001. Intensive insulin

M.W., Serlie, M.J., van der Poll, T., & Sauerwein, H.P. 2009. Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans. *J Clin* 

immunity in the progression of alcohol-mediated liver injury. *Trends Mol Med*.

under stomach conditions is modulated by reducing compounds. *Free Radic Biol* 

sensitivity to endotoxin liver injury: implications for the pathogenesis of

inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic

Yokoyama, A., Takagi, S., & Hayashida, M. 1997. Alcohol-related sudden death with hepatic fatty metamorphosis: a comprehensive clinicopathological inquiry

alcoholic fatty liver disease in a population-based study and its association with

and clinical implications. *Diabetes*. 44:863-70.

lipid metabolism. *Diabetologia*. 49:1732-41. Weinberg, J.M. 2006. Lipotoxicity. *Kidney Int*. 70:1560-6.

steatohepatitis. *Proc Natl Acad Sci U S A*. 94:2557-62.

into its pathogenesis. *Alcohol Alcohol*. 32:745-52.

fatty liver disease pathophysiology. *Hepatology*. 34:694-706.

biochemical and anthropometric measures. *Liver Int*. 26:856-63.

16:379-414.

14:63-71.

*Med*. 47:496-502.

*Endocrinol Metab*. 94:463-8.


Oguri, S., Motegi, K., Iwakura, Y., & Endo, Y. 2002. Primary role of interleukin-1 alpha and

Pietraszek, A., Gregersen, S., & Hermansen, K. 2010. Alcohol and type 2 diabetes. A review.

Platia, E.V., & Hsu, T.H. 1979. Hypoglycemic coma with ketoacidosis in nondiabetic

Raddatz, D., & Ramadori, G. 2007. Carbohydrate metabolism and the liver: actual aspects

Rai, R.M., Lee, F.Y., Rosen, A., Yang, S.Q., Lin, H.Z., Koteish, A., Liew, F.Y., Zaragoza, C.,

Rector, R.S., Thyfault, J.P., Wei, Y., & Ibdah, J.A. 2008. Non-alcoholic fatty liver disease and

Riehle, K.J., Dan, Y.Y., Campbell, J.S., & Fausto, N. 2011. New concepts in liver regeneration.

Samuel, V.T., Petersen, K.F., & Shulman, G.I. 2010. Lipid-induced insulin resistance:

Shimano, H. 2007. SREBP-1c and TFE3, energy transcription factors that regulate hepatic

Sneyd, J.G.T. 1989. Interactions of ethanol and carbohydrate metabolism. Boca Raton, FL:

Song, Z., Zhou, Z., Deaciuc, I., Chen, T., & McClain, C.J. 2008. Inhibition of adiponectin

Spiekerkoetter, U., & Wood, P.A. 2010. Mitochondrial fatty acid oxidation disorders:

Suzuki, A., Uno, M., Arima, K., Obana, M., Matsuoka, Y., Irimajiri, S., & Fukuda, J. 1994. [A

Szabo, G., Romics, L., Jr., & Frendl, G. 2002. Liver in sepsis and systemic inflammatory

Tabassum, F., Khurshid, R., Karim, S., & Akhtar, M.S. 2001. Metabolic effects of alcoholism

Targher, G., Bertolini, L., Padovani, R., Rodella, S., Tessari, R., Zenari, L., Day, C., & Arcaro,

Tirosh, O., Artan, A., Aharoni-Simon, M., Ramadori, G., & Madar, Z. 2010. Impaired liver

pathophysiological studies in mouse models. *J Inherit Metab Dis*.

production by homocysteine: a potential mechanism for alcoholic liver disease.

case report: sepsis associated with hypoglycemia]. Kansenshogaku Zasshi. 68:986-9.

and its relationship with alcoholic liver disease. *J Ayub Med Coll Abbottabad*. 13:19-

G. 2007. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 30:1212-8.

glucose production in a murine model of steatosis and endotoxemia: protection by

oxide synthasedeficient mice. *Proc Natl Acad Sci U S A*. 95:13829-34. Randall, B. 1980. Fatty liver and sudden death. A review. *Hum Pathol*. 11:147-53.

the metabolic syndrome: an update. *World J Gastroenterol*. 14:185-92.

Lowenstein, C., & Diehl, A.M. 1998. Impaired liver regeneration in inducible nitric

Orford, N.R. 2006. Intensive insulin therapy in septic shock. *Crit Care Resusc*. 8:230-4.

from physiology and disease. *Z Gastroenterol*. 45:51-62.

*Lab Immunol*. 9:1307-12.

*Nutr Metab Cardiovasc Dis*.

alcoholics. *West J Med*. 131:270-6.

*J Gastroenterol Hepatol*. 26 Suppl 1:203-12.

insulin signaling. *J Mol Med*. 85:437-44.

CRC Press, . 115-124 pp.

*Hepatology*. 47:867-79.

21.

unravelling the mechanism. *Lancet*. 375:2267-77.

response syndrome. *Clin Liver Dis*. 6:1045-66, x.

Thompson, B.T. 2008. Glucose control in sepsis. *Clin Chest Med*. 29:713-20, x.

inducible nitric oxide synthase. *Antioxid Redox Signal*. 13:13-26.

interleukin-1 beta in lipopolysaccharide-induced hypoglycemia in mice. *Clin Diagn* 


**6** 

*USA* 

**Postprandial Hypoglycemia** 

Mubeen Khan1 and Udaya M. Kabadi2,3,4

*Iowa Methodist Medical Center, Des Moines, Iowa* 

*1University of Iowa-Des Moines Internal Medicine Residency Program at* 

Postprandial hypoglycemia is a syndrome secondary to disorders in which hypoglycemia is manifested within 5 hours after a meal (1). It is classified into two types depending on the time of occurrence, i.e., 'early,' with onset within 2 hours, and 'late,' occurring between 3 and 5 hours after a meal. The early variety is thought to be secondary to abnormally rapid gastric emptying, whereas late postprandial hypoglycemia is frequently deemed to be a precursor to the onset of type 2 diabetes mellitus (1-14). Causes of late postprandial hypoglycemia also include disorders manifesting as fasting hypoglycemia, such as factitious hypoglycemia due to exogenous insulin administration or surreptitious use of insulin secretogogues, e.g, sulfonylureas, glinides, or other hypoglycemic agents, insulinoma, islet cell hyperplasia, autoimmune hyperinsulinemia, hyperinsulinemia caused by drugs and toxins, excess of circulating IGF2 secreted by non-pancreatic tumors, adrenal or pituitary hypofunction, advanced liver dysfunction, and end-stage renal disease(15-29 ) Several rare disorders, including some congenital syndromes, e.g., glycogen storage disorders, can also cause late postprandial hypoglycemia(30). In contrast, early postprandial hypoglycemia occurs only postprandially and usually is noted in subjects following upper gastrointestinal surgery, including bariatric procedures, hyperthyroidism, etc (1,21,26,31,32). In some subjects, it occurs without an obvious apparent cause and is therefore termed 'idiopathic reactive hypoglycemia.' Arguably, many endocrinologists approve of this syndrome, whereas others question its existence and call it 'postprandial syndrome,' probably because

Hypoglycemia presents with manifestations of increased sympathetic activity, i.e., anxiety, jitters, palpitations, dizziness, tremor, weakness, drenching perspiration, hunger, systolic hypertension, mydriasis, etc., attributed to prompt release of catecholamines, which is documented to occur with a fall of blood sugar to lower than 70 mg /dl (29,34,35). Manifestations more seriously detrimental to life, i.e., of a neuroglycopenic nature, include convulsion, confusion, coma, or other altered states of consciousness, and transient CNS manifestations, including hemiparesis. Cardiac manifestations include symptomatic coronary artery disease, i.e., angina pectoris, arrhythmias, or even myocardial infarction following extreme lowering of blood sugars, usually to concentrations below 50 mg/dl (35).

of the debate over the diagnosis of hypoglycemia itself (8,21,29).

**1. Introduction** 

*2Veterans Affairs Medical Center, Iowa Methodist Medical Center, 3Des Moines University of Osteopathic Medicine, Des Moines, Iowa, 4University of Iowa Carver College of Medicine, Iowa City, Iowa,* 


## **Postprandial Hypoglycemia**

### Mubeen Khan1 and Udaya M. Kabadi2,3,4

*1University of Iowa-Des Moines Internal Medicine Residency Program at Iowa Methodist Medical Center, Des Moines, Iowa 2Veterans Affairs Medical Center, Iowa Methodist Medical Center, 3Des Moines University of Osteopathic Medicine, Des Moines, Iowa, 4University of Iowa Carver College of Medicine, Iowa City, Iowa, USA* 

### **1. Introduction**

116 Diabetes – Damages and Treatments

Zeng, M.D., Li, Y.M., Chen, C.W., Lu, L.G., Fan, J.G., Wang, B.Y., & Mao, Y.M. 2008.

Zhou, Y.J., Li, Y.Y., Nie, Y.Q., Ma, J.X., Lu, L.G., Shi, S.L., Chen, M.H., & Hu, P.J. 2007.

Zivkovic, A.M., German, J.B., & Sanyal, A.J. 2007. Comparative review of diets for the

9:113-6.

*Nutr*. 86:285-300.

China. *World J Gastroenterol*. 13:6419-24.

Guidelines for the diagnosis and treatment of alcoholic liver disease. *J Dig Dis*.

Prevalence of fatty liver disease and its risk factors in the population of South

metabolic syndrome: implications for nonalcoholic fatty liver disease. *Am J Clin* 

Postprandial hypoglycemia is a syndrome secondary to disorders in which hypoglycemia is manifested within 5 hours after a meal (1). It is classified into two types depending on the time of occurrence, i.e., 'early,' with onset within 2 hours, and 'late,' occurring between 3 and 5 hours after a meal. The early variety is thought to be secondary to abnormally rapid gastric emptying, whereas late postprandial hypoglycemia is frequently deemed to be a precursor to the onset of type 2 diabetes mellitus (1-14). Causes of late postprandial hypoglycemia also include disorders manifesting as fasting hypoglycemia, such as factitious hypoglycemia due to exogenous insulin administration or surreptitious use of insulin secretogogues, e.g, sulfonylureas, glinides, or other hypoglycemic agents, insulinoma, islet cell hyperplasia, autoimmune hyperinsulinemia, hyperinsulinemia caused by drugs and toxins, excess of circulating IGF2 secreted by non-pancreatic tumors, adrenal or pituitary hypofunction, advanced liver dysfunction, and end-stage renal disease(15-29 ) Several rare disorders, including some congenital syndromes, e.g., glycogen storage disorders, can also cause late postprandial hypoglycemia(30). In contrast, early postprandial hypoglycemia occurs only postprandially and usually is noted in subjects following upper gastrointestinal surgery, including bariatric procedures, hyperthyroidism, etc (1,21,26,31,32). In some subjects, it occurs without an obvious apparent cause and is therefore termed 'idiopathic reactive hypoglycemia.' Arguably, many endocrinologists approve of this syndrome, whereas others question its existence and call it 'postprandial syndrome,' probably because of the debate over the diagnosis of hypoglycemia itself (8,21,29).

Hypoglycemia presents with manifestations of increased sympathetic activity, i.e., anxiety, jitters, palpitations, dizziness, tremor, weakness, drenching perspiration, hunger, systolic hypertension, mydriasis, etc., attributed to prompt release of catecholamines, which is documented to occur with a fall of blood sugar to lower than 70 mg /dl (29,34,35). Manifestations more seriously detrimental to life, i.e., of a neuroglycopenic nature, include convulsion, confusion, coma, or other altered states of consciousness, and transient CNS manifestations, including hemiparesis. Cardiac manifestations include symptomatic coronary artery disease, i.e., angina pectoris, arrhythmias, or even myocardial infarction following extreme lowering of blood sugars, usually to concentrations below 50 mg/dl (35).

Postprandial Hypoglycemia 119

to 5 hours or at the onset of symptoms of hypoglycemia following ingestion of a mixed meal

The occurrence of postprandial hypoglycemia within 2 hours is attributed to an exaggerated insulin response to markedly elevated plasma glucose levels within 15-30 minutes caused by a prompt absorption of carbohydrate content, especially the simple variety due to a super fast transit of an ingested meal across the stomach as initially documented in subjects undergoing gastric surgery e.g. partial or total gastrectomy for several decades and more recently in morbidly obese subjects undergoing gastric bypass surgery(1,54,8,20,21,26) In fact ,we believe that persistent occurrence of hypoglycemia irrespective of timing of the meal during the later years following gastric bypass surgery may attributed to repeated frequent postprandial stimulation of pancreatic beta cells ultimately leading to autonomous beta cell hyperplasia requiring excision (26) .Surgery may be prevented by appropriate dietary changes as well as a prompt therapy with medications during the initial period

In the absence of documentation of a known disorder, early postprandial hypoglycemia is also termed 'Idiopathic reactive hypoglycemia' by some and 'postprandial syndrome' by others. We firmly believe that 'Idiopathic reactive hypoglycemia' is a genuine disorder, since several pathophysiologic mechanisms have been implicated (2-14).The occurrence of hypoglycemia in this disorder has been attributed to rapid gastric emptying secondary to lack of rise in Gastric Inhibitory Polypeptide following an ingestion of a meal or altered secretion of other gastrointestinal motility factors,e.g.Motilin, Bombesin etc(1-4) Remission of hypoglycemia by inhibition of gastric emptying by use of drugs with ability to induce cholinergic blockade enhances this hypothesis. Alternatively, altered function of both pancreatic alpha and beta cells has also been invoked. We have documented enhanced 1st or early phase insulin secretion within 30-60 minutes in response to glucose ingestion as well as aberrant pancreatic alpha cell function in this syndrome (Table 1). plasma glucagon is elevated after an overnight fast in comparison to normal subjects despite presence of normal glucose concentration indicating glucagon insensitivity (Table1). However, inhibited glucagon decline with initial hyperglycemia and a blunted rise following onset of hypoglycemia documents altered glucagon secretion in this syndrome.(Figure1) Impaired regulation of glucagon in this syndrome is further confirmed by decline in glucagon response following oral administration of a protein meal (figure 2), a well established stimulus for facilitating glucagon secretion and release by pancreatic alpha cells(41).This altered pancreatic alpha and beta cell function is also documented in several other studies (7,9,1,33,40). Finally, the presence of the disorder is further enhanced by documentation of remission of symptoms and hypoglycemia by appropriate intervention with several protocols, including lifestyle changes with use of a diet with tolerated amount of fiber as well as high protein, low carbohydrate contents, avoidance of ingestion of simple or free sugars, and frequent small feedings (1,5,14 ). Moreover, in the absence of total remission with these lifestyle changes, several drugs have been successfully used. These include agents, e.g. atropine derivatives which delay gastric emptying by cholinergic blockade as mentioned earlier, drugs inhibiting conversion of complex to simple carbohydrates,e.g.alpha-glucosidase inhibitors, medications altering insulin secretion e.g.calcium channel blockers, or drugs possessing all of these properties, e.g. octreotide (3,42-47). In contrast, 'late reactive or postrprandial hypoglycemia'documented in 'impaired glucose tolerance', a prediabetic state is induced by exaggerated 2nd or late phase insulin

or glucose (OGGT) often clinches the diagnosis.

following a bariatric procedure (42-47)

Few authorities still believe that the onset of manifestations of exaggerated sympathetic activity may be dependent on the rapidity of rate of fall in blood glucose irrespective of the exact concentration, although several studies have refuted this hypothesis.

Therefore, in subjects with diabetes, hypoglycemia is deemed to occur with the onset of symptoms even when the blood sugar is between 50 and 70 mg/dl. Moreover, blood sugars lower than 70 mg/dl in the absence of manifestations of sympathetic overactivity are also defined as hypoglycemia and the subject is deemed to manifest hypoglycemia unawareness (36-38). Finally, all efforts are made to prevent 'hypoglycemia' in both these circumstances frequently by altering the treatment plan. In contrast, several authorities promote that the diagnosis of hypoglycemia should be made in the presence of blood sugar <50 mg/dl and that too only if criteria for Whipple's triad are fulfilled (39). The triad consists of documentation of a blood sugar <50 mg/dl accompanied by symptoms of hypoglycemia, and resolution of symptoms by inducing a rise in blood sugar by either ingestion of sugar or a meal, or iv administration of glucose.

Thus, according to these authors, subjects with documentation of a blood sugar < 50 mg/dl, after an overnight fast, postprandially, or randomly, deserve evaluation in the absence of diabetes mellitus only if the low blood sugar is accompanied by symptoms (21,26,29),. The recommendation is totally different in the presence of diabetes. In subjects with diabetes, a thorough assessment of hypoglycemic symptoms and even asymptomatic low blood sugar is recommended. Therefore, in the absence of symptoms, in non-diabetic subjects, a blood sugar < 50 mg/dl is not defined as a syndrome of 'hypoglycemia' by these authors. However, this concept is in stark contrast to the tenet of ethical medical practice to define and treat disorders with definite documentation of metabolic abnormalities despite the absence of symptoms, e.g., hyperglycemia, hypercalcemia, changes in sodium and potassium concentrations, and many other medical disorders, including subclinical hypo and hyperthyroidism. This practice is obviously prudent in the light of clear documentation of increased morbidity and even mortality of subclinical disorders, especially with lack of restoration of the normal state. Furthermore, restoring and preserving the normal state with appropriate treatment is also documented to improve the quality of life in these subjects manifesting subclinical disorders. Therefore, it is difficult to fathom why the same principle is not applied in the management of well documented postprandial hypoglycemia in the absence of typical symptoms or frequently even in the presence of characteristic manifestations.

We firmly believe that postprandial hypoglycemia is a 'true' disorder with a distinct deterioration in quality of life, including attention deficit and loss of productivity (1,9 - 14,40),. Moreover, a cause of the abnormality is easily determined by a detailed history, a thorough physical examination, and simple laboratory testing. A history of upper gastrointestinal surgery for esophageal and gastric diseases, bariatric procedures, symptoms of hyperthyroidism, the timing of the occurrence of symptoms following a meal, i.e., 'early' or 'late' onset, dietary pattern provoking symptoms, i.e., high carbohydrate content or ingestion of simple sugars, changes in body weight, use of certain drugs, history of gestational diabetes; all provide clues to indicate a specific diagnosis. Family history of type 2 diabetes mellitus is important information as well. Similarly, a thorough physical examination may indicate the presence of a specific disorder. Finally, the determination of appropriate laboratory tests after an overnight fast and at frequent (30 minute) intervals, up

Few authorities still believe that the onset of manifestations of exaggerated sympathetic activity may be dependent on the rapidity of rate of fall in blood glucose irrespective of the

Therefore, in subjects with diabetes, hypoglycemia is deemed to occur with the onset of symptoms even when the blood sugar is between 50 and 70 mg/dl. Moreover, blood sugars lower than 70 mg/dl in the absence of manifestations of sympathetic overactivity are also defined as hypoglycemia and the subject is deemed to manifest hypoglycemia unawareness (36-38). Finally, all efforts are made to prevent 'hypoglycemia' in both these circumstances frequently by altering the treatment plan. In contrast, several authorities promote that the diagnosis of hypoglycemia should be made in the presence of blood sugar <50 mg/dl and that too only if criteria for Whipple's triad are fulfilled (39). The triad consists of documentation of a blood sugar <50 mg/dl accompanied by symptoms of hypoglycemia, and resolution of symptoms by inducing a rise in blood sugar by either ingestion of sugar or

Thus, according to these authors, subjects with documentation of a blood sugar < 50 mg/dl, after an overnight fast, postprandially, or randomly, deserve evaluation in the absence of diabetes mellitus only if the low blood sugar is accompanied by symptoms (21,26,29),. The recommendation is totally different in the presence of diabetes. In subjects with diabetes, a thorough assessment of hypoglycemic symptoms and even asymptomatic low blood sugar is recommended. Therefore, in the absence of symptoms, in non-diabetic subjects, a blood sugar < 50 mg/dl is not defined as a syndrome of 'hypoglycemia' by these authors. However, this concept is in stark contrast to the tenet of ethical medical practice to define and treat disorders with definite documentation of metabolic abnormalities despite the absence of symptoms, e.g., hyperglycemia, hypercalcemia, changes in sodium and potassium concentrations, and many other medical disorders, including subclinical hypo and hyperthyroidism. This practice is obviously prudent in the light of clear documentation of increased morbidity and even mortality of subclinical disorders, especially with lack of restoration of the normal state. Furthermore, restoring and preserving the normal state with appropriate treatment is also documented to improve the quality of life in these subjects manifesting subclinical disorders. Therefore, it is difficult to fathom why the same principle is not applied in the management of well documented postprandial hypoglycemia in the absence of typical symptoms or frequently even in the presence of characteristic

We firmly believe that postprandial hypoglycemia is a 'true' disorder with a distinct deterioration in quality of life, including attention deficit and loss of productivity (1,9 - 14,40),. Moreover, a cause of the abnormality is easily determined by a detailed history, a thorough physical examination, and simple laboratory testing. A history of upper gastrointestinal surgery for esophageal and gastric diseases, bariatric procedures, symptoms of hyperthyroidism, the timing of the occurrence of symptoms following a meal, i.e., 'early' or 'late' onset, dietary pattern provoking symptoms, i.e., high carbohydrate content or ingestion of simple sugars, changes in body weight, use of certain drugs, history of gestational diabetes; all provide clues to indicate a specific diagnosis. Family history of type 2 diabetes mellitus is important information as well. Similarly, a thorough physical examination may indicate the presence of a specific disorder. Finally, the determination of appropriate laboratory tests after an overnight fast and at frequent (30 minute) intervals, up

exact concentration, although several studies have refuted this hypothesis.

a meal, or iv administration of glucose.

manifestations.

to 5 hours or at the onset of symptoms of hypoglycemia following ingestion of a mixed meal or glucose (OGGT) often clinches the diagnosis.

The occurrence of postprandial hypoglycemia within 2 hours is attributed to an exaggerated insulin response to markedly elevated plasma glucose levels within 15-30 minutes caused by a prompt absorption of carbohydrate content, especially the simple variety due to a super fast transit of an ingested meal across the stomach as initially documented in subjects undergoing gastric surgery e.g. partial or total gastrectomy for several decades and more recently in morbidly obese subjects undergoing gastric bypass surgery(1,54,8,20,21,26) In fact ,we believe that persistent occurrence of hypoglycemia irrespective of timing of the meal during the later years following gastric bypass surgery may attributed to repeated frequent postprandial stimulation of pancreatic beta cells ultimately leading to autonomous beta cell hyperplasia requiring excision (26) .Surgery may be prevented by appropriate dietary changes as well as a prompt therapy with medications during the initial period following a bariatric procedure (42-47)

In the absence of documentation of a known disorder, early postprandial hypoglycemia is also termed 'Idiopathic reactive hypoglycemia' by some and 'postprandial syndrome' by others. We firmly believe that 'Idiopathic reactive hypoglycemia' is a genuine disorder, since several pathophysiologic mechanisms have been implicated (2-14).The occurrence of hypoglycemia in this disorder has been attributed to rapid gastric emptying secondary to lack of rise in Gastric Inhibitory Polypeptide following an ingestion of a meal or altered secretion of other gastrointestinal motility factors,e.g.Motilin, Bombesin etc(1-4) Remission of hypoglycemia by inhibition of gastric emptying by use of drugs with ability to induce cholinergic blockade enhances this hypothesis. Alternatively, altered function of both pancreatic alpha and beta cells has also been invoked. We have documented enhanced 1st or early phase insulin secretion within 30-60 minutes in response to glucose ingestion as well as aberrant pancreatic alpha cell function in this syndrome (Table 1). plasma glucagon is elevated after an overnight fast in comparison to normal subjects despite presence of normal glucose concentration indicating glucagon insensitivity (Table1). However, inhibited glucagon decline with initial hyperglycemia and a blunted rise following onset of hypoglycemia documents altered glucagon secretion in this syndrome.(Figure1) Impaired regulation of glucagon in this syndrome is further confirmed by decline in glucagon response following oral administration of a protein meal (figure 2), a well established stimulus for facilitating glucagon secretion and release by pancreatic alpha cells(41).This altered pancreatic alpha and beta cell function is also documented in several other studies (7,9,1,33,40). Finally, the presence of the disorder is further enhanced by documentation of remission of symptoms and hypoglycemia by appropriate intervention with several protocols, including lifestyle changes with use of a diet with tolerated amount of fiber as well as high protein, low carbohydrate contents, avoidance of ingestion of simple or free sugars, and frequent small feedings (1,5,14 ). Moreover, in the absence of total remission with these lifestyle changes, several drugs have been successfully used. These include agents, e.g. atropine derivatives which delay gastric emptying by cholinergic blockade as mentioned earlier, drugs inhibiting conversion of complex to simple carbohydrates,e.g.alpha-glucosidase inhibitors, medications altering insulin secretion e.g.calcium channel blockers, or drugs possessing all of these properties, e.g. octreotide (3,42-47). In contrast, 'late reactive or postrprandial hypoglycemia'documented in 'impaired glucose tolerance', a prediabetic state is induced by exaggerated 2nd or late phase insulin

Postprandial Hypoglycemia 121

Fig. 1. Glucose, insulin, and glucagon responses to oral ingestion of 100 g glucose(OGTT) in 5 subjects with IRH (▲) and 6 normal subjects () \* P< .01 v normal. Reprinted from

reference 12, with permission

secretion occurring between 90 -120 minutes induced by marked elevated plasma glucose concentration at 60-90 minutes due to inhibition of 1`st phase insulin secretion following a meal or oral administration of glucose (48-52)).Moreover, hypoglycemia in this disorder also is remediable by appropriate lifestyle changes and certain drugs (53).

Therefore, A subject manifesting symptoms of hypoglycemia following a meal must be evaluated by a detailed history, a thorough physical examination and appropriate laboratory testing. First and foremost, the presence of low blood sugar level, e.g < 6O mg/dl must be documented with accompanying hypoglycemic symptoms. The diagnosis could be further established by assessment of blood sugars following ingestion of a mixed meal or oral administration of glucose. Once the diagnosis is confirmed, the appropriate treatment should be provided as it distinctly improves quality of life. Early postprandial hypoglycemia with onset within 2 hours may be treated with life style dietary changes initially. The drugs may be used later as an adjunctive therapy if dietary manipulations fail to attain and maintain remission. The documentation of late reactive hypoglycemia indicates a presence of 'Prediabetes' which also may be managed with lifestyle changes, e.g. diet and exercise, to achieve weight loss especially in the obese subjects as well as with drugs, e.g. Metformin in subjects with increased risk for progression to Diabetes as recommended by American Diabetes Association(48),

Therefore, in the final analysis, it is imperative to consider the presence of postprandial hypoglycemia as a disorder and conduct an appropriate evaluation and provide suitable therapeutic strategies.


\* The average of 2 values in individual subjects, 1 during the OGTT and the other during the protein meal study, was used for calculation.

† P< .025, IRH v normal.

Reprinted from reference 12, with permission

Table 1. Fasting Plasma Glucose, Insulin,and Glucagon Levels in Five Subjects With IRH and Six Normal Subjects.

secretion occurring between 90 -120 minutes induced by marked elevated plasma glucose concentration at 60-90 minutes due to inhibition of 1`st phase insulin secretion following a meal or oral administration of glucose (48-52)).Moreover, hypoglycemia in this disorder also

Therefore, A subject manifesting symptoms of hypoglycemia following a meal must be evaluated by a detailed history, a thorough physical examination and appropriate laboratory testing. First and foremost, the presence of low blood sugar level, e.g < 6O mg/dl must be documented with accompanying hypoglycemic symptoms. The diagnosis could be further established by assessment of blood sugars following ingestion of a mixed meal or oral administration of glucose. Once the diagnosis is confirmed, the appropriate treatment should be provided as it distinctly improves quality of life. Early postprandial hypoglycemia with onset within 2 hours may be treated with life style dietary changes initially. The drugs may be used later as an adjunctive therapy if dietary manipulations fail to attain and maintain remission. The documentation of late reactive hypoglycemia indicates a presence of 'Prediabetes' which also may be managed with lifestyle changes, e.g. diet and exercise, to achieve weight loss especially in the obese subjects as well as with drugs, e.g. Metformin in subjects with increased risk for progression to Diabetes as

Therefore, in the final analysis, it is imperative to consider the presence of postprandial hypoglycemia as a disorder and conduct an appropriate evaluation and provide suitable

> Fasting Plasma Glucose (mmol/L)\*

IHR 37±6 59±8 4.9±0.2 7±2 347±83†

Normal 34±5 62±7 5.2±0.1 6±1 135±20

\* The average of 2 values in individual subjects, 1 during the OGTT and the other during the protein

Table 1. Fasting Plasma Glucose, Insulin,and Glucagon Levels in Five Subjects With IRH and

Fasting Plasma Insulin (mU/L)\*

Fasting Plasma Glucagon (ng/L)\*

is remediable by appropriate lifestyle changes and certain drugs (53).

recommended by American Diabetes Association(48),

therapeutic strategies.

Group Age

meal study, was used for calculation.

Reprinted from reference 12, with permission

† P< .025, IRH v normal.

Six Normal Subjects.

(yr)

Body Weight (kg)

Fig. 1. Glucose, insulin, and glucagon responses to oral ingestion of 100 g glucose(OGTT) in 5 subjects with IRH (▲) and 6 normal subjects () \* P< .01 v normal. Reprinted from reference 12, with permission

Postprandial Hypoglycemia 123

[2] O'Keefe SJ, Marks V. Lunchtime gin and tonic as a cause of reactive hypoglycemia.

[3] Permutt MA, Keller D, Santiago J.Cholinergic blockade in reactive hypoglycemia.

[4] Lev-Ran A, Anderson RW The diagnosis of postprandial hypoglycemia. Diabetes. 1981

[7] Tamburrano G, Leonetti F, Sbraccia P, Giaccari A, Locuratolo N, Lala A Increased insulin

[8] Hofeldt FD.Reactive hypoglycemia. Endocrinol Metab Clin North Am. 1989

[9] Leonetti F, Morviducci L, Giaccari A, Sbraccia P, Caiola S, Zorretta D, Lostia O,

[10] Berlin I, Grimaldi A, Landault C, Cesselin F, Puech AJ Suspected postprandial

[11] Leonetti F, Foniciello M, Iozzo P, Riggio O, Merli M, Giovannetti P, Sbraccia P, Giaccari

[12] Ahmadpour S, Kabadi UM.Pancreatic alpha-cell function in idiopathic reactive

[13] Altuntas Y, Bilir M, Ucak S, Gundogdu S. Reactive hypoglycemia in lean young

[15] Kogut MD, Blaskovics M, Donnell GN, et al. Idiopathic hypoglycemia: a study of

[16] Bressler R, Corredor C, Brendel K. Hypoglycin and hypoglycin-like compounds.

[17] Merimee TJ, Felif P, Marliss E, et al. Glucose and lipid homeostasis in the absence of

[19] Cryer PE. Glucose counterregulation: prevention and correction of hypoglycemia in

function. Eur J Obstet Gynecol Reprod Biol. 2005 Apr 1;119(2):198-205. [14] Sørensen M, Johansen OE Idiopathic reactive hypoglycaemia - prevalence and

distress. J Clin Endocrinol Metab. 1994 Nov;79(5):1428-33.

reactive hypoglycemia. Metabolism. 1996 May;45(5):606-10.

hypoglycemia. Metabolism. 1997 Jun;46(6):639-43.

twenty-six children. J Pediatr. 1969;74:853-871

humans. Am J Physiol. 1993;264:E149-E155

human growth hormone. J Clin Invest. 1971;50:574-582 [18] Service FJ. Factitial hypoglycemia. Endocrinologist. 1992;2:173- 176.

Pharmacol Rev. 1969;21:105-130

symptomatic episodes in patients with suspected postprandial hypoglycemia. N

sensitivity in patients with idiopathic reactive hypoglycemia. J Clin Endocrinol

Tamburrano G Idiopathic reactive hypoglycemia: a role for glucagon? J Endocrinol

hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional

A, Tamburrano G Increased nonoxidative glucose metabolism in idiopathic

women with PCOS and correlations with insulin sensitivity and with beta cell

effect of fibre on glucose excursions.Scand J Clin Lab Invest. 2010 Oct;70(6):385-

[5] Betteridge DJ Reactive hypoglycaemia. Br Med J (Clin Res Ed). 1987 Aug 1;295:286-7. [6] Palardy J, Havrankova J, Lepage R, et al. Blood glucose measurements during

[1] Kunkel S, Kabadi,U Non-diabetic hypoglycemia BMJ Point of Care,2011

**2. References** 

Lancet. 1977;1:1286-1288

Dec;30(12):996-9.

Mar;18(1):185-201

91

Diabetes. 1977 Feb;26(2):121-7.

Engl J Med. 1989;321:1421-1425

Metab. 1989 Oct;69(4):885-90.

Invest. 1992 Apr;15(4):273-8.

Fig. 2. Glucose, insulin, and glucagon responses to oral ingestion of a protein meal in 5 subjects with IRH (▲) and 6 normal subjects (). \* < .05 v normal. † P< .01 IRH. Reprinted from reference 12, with permission

### **2. References**

122 Diabetes – Damages and Treatments

Fig. 2. Glucose, insulin, and glucagon responses to oral ingestion of a protein meal in 5 subjects with IRH (▲) and 6 normal subjects (). \* < .05 v normal. † P< .01 IRH. Reprinted

from reference 12, with permission


Postprandial Hypoglycemia 125

[38] Weber KK, Lohmann T, Busch K, Donati-Hirsch I, Riel R. High frequency of

[41] Kabadi UM.Dose-kinetics of pancreatic alpha- and beta-cell responses to a protein

[42] Richard JL, Rodier M, Monnier L, Orsetti A, Mirouze J Effect of acarbose on glucose

[43] Peter S. Acarbose and idiopathic reactive hypoglycemia. Horm Res, 2003;60(4):166-

[44] Renard E, Parer-Richard C, Richard JL, Jureidini S, Orsetti A, Mirouze J.Effect of

[45] Sanke T, Nanjo K, Kondo M, Ni M, Moriyama Y Effect of calcium antagonists on

[46] Baschieri L, Antonelli A, del Guerra P, Fialdini A, Gasperini L. Somatostatin effect in

[47] Weyer C., Bogardus C., Mott D.M., Pratley R.E. (1999) The natural

[48] Kabadi MU, Kabadi, UM. Effects of glimepiride on insulin secretion and sensitivity in

[49] Ferrannini E., Gastaldelli A., Miyazaki Y., Matsuda M., Mari A., DeFronzo R.A.B-cell

[50] Abdul-Ghani M.A., Tripathy D., Jenckinson C., Ritchardson D., DeFronzo

postprandial hypoglycemia. Metabolism. 1989 Jun;38(6):568-71.

[39] Whipple AOThe Surgical Therapy of Hyperinsulinoma J.Int Chir 3:237, 1938 [40] Kabadi UM and Kabadi MU Idiopathic Reactive Hypoglycemia: Resolution on

meal in normal subjects. Metabolism. 1991 Mar;40(3):236-40

750-6.

491-4

568,June 2006

,14(2):114-8.

7.

62.

71.

787-794.

26(1) 2004

500. 2005

2006

Type 2 diabetes: a cross-sectional survey. Diabet Med. 2006 Jul;23(7):

unrecognized hypoglycaemias in patients with Type 2 diabetes is discovered by continuous glucose monitoring. Exp Clin Endocrinol Diabetes. 2007 Sep;115(8):

Increased Protein Intake secondary to Decreased Insulin Response with Enhanced Glucagon Rise. Endocrine Society Annual Meeting ,Page 540,Absract no P2-

and insulin response to sucrose load in reactive hypoglycemia. Diabete Metab. 1988

Miglitol (Bay m1099), a new alpha-glucosidase inhibitor, on glucose, insulin, C-peptide and GIP responses to an oral sucrose load in patients with postprandial hypoglycaemic symptoms. Diabete Metab. 1991 May-Jun;17(3):355-

reactive hypoglycemia associated with hyperinsulinemia. MetabolismJun;38(6):568-

history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. *The Journal of Clinical Investigation*, 104,

patients with recently diagnosed type 2 diabetes mellitus. Clinical Therapeutics

function in subjects spanning the range from normal glucose Tolerance to overt diabetes: A new analysis. *The Journal of Clinical Endocrinology & Metabolism.* 90, 493-

R.A.Insulin secretion and insulin action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study (VEGAS). *Diabetes,* 55, 1430-1435.


[20] Marks V, Teale JD Hypoglycaemia in the adult. Baillieres Clin Endocrinol Metab. 1993

[22] Fischer KF, Lees JA, Newman JH, et al. Hypoglycemia in hospitalized patients: causes

[23] Hizuka N, Fukuda I, Takano K, et al. Serum insulin-like growth factor II in 44 patients

[24] Cavaco B, Uchigata Y, Porto T, Amparo-Santos M, Sobrinho L, Leite V

[25] Kim CH, Park JH, Park TS, et al. Autoimmune hypoglycemia in a type 2 diabetic

[26] Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with

[27] Karachaliou R, Vlachopapadopoulou E, Kaldrymidis P, et al. Malignant insulinoma in

[28] Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: drug-induced

[29] Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult

[30] Talente GM, Coleman RA, Alter C, et al. Glycogen storage disease in adults. Ann

[31] Kabadi UM and Eisenstein AB Glucose Intolerance in Hyperthyroidism:Role of

[32] Kabadi UM, Eisenstein AB. Impaired pancreatic @-cell response in hyperthyroidism. J

[33] Kabadi UM Hepatic regulation of pancreatic alpha-cell function. Metabolism. 1993

[34] Cryer PE Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005 Dec;54(12):3592-601. [35] Cryer PE Hypoglycemia, functional brain failure, and brain death.J Clin Invest. 2007

[36] Arbelaez AM, Powers WJ, Videen TO, Price JL,Cryer PE Attenuation of

[37] Akram K, Pedersen-Bjergaard U, Carstensen B, Borch-Johnsen K, Thorsteinsson B

counterregulatory responses to recurrent hypoglycemia by active thalamic inhibition: a mechanism for hypoglycemia-associated autonomic failure. Diabetes.

Frequency and risk factors of severe hypoglycaemia in insulin-treated

childhood. J Pediatr Endocrinol Metab. 2006;19:757-760

Glucagon J Clin Endocrinol Metab50:392-396,1980

Endocrinol Metab. 2009;94:709-728.

Intern Med. 1994;120:218-226

Clin Endo Metab 51:478, 1980.

May;42(5):535-43.

Apr;117(4):868-70

2008 Feb;57(2):470-5.

Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies. Eur J Endocrinol.

patient with anti-insulin and insulin receptor antibodies. Diabetes Care.

nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353:

hypoglycemia: a systematic review. J Clin Endocrinol Metab. 2009;94:

hypoglycemic disorders: an Endocrine Society clinical practice guideline. J Clin

with non-islet cell tumor hypoglycemia. Endocr J. 1998;45:S61-S65

[21] Service FJ.Hypoglycemic disorders. N Engl J Med. 1995;332:1144-1152

and outcomes. N Engl J Med. 1996;315:1245-1250

Jul;7(3):705-29.

2001 Sep;145(3):311-6.

2004;27:288-289

249-254

741-745.

Type 2 diabetes: a cross-sectional survey. Diabet Med. 2006 Jul;23(7): 750-6.


**7** 

Stephen F. Kemp

*U. S. A.* 

*Arkansas Children's Hospital* 

**The Role of the Pituitary-Growth** 

*University of Arkansas for Medical Sciences* 

**Hormone-IGF Axis in Glucose Homeostasis** 

Hypoglycemia results when either carbohydrate intake is low, tissue use is high (glycolysis or glucagons synthesis), or endogenous production of glucose is low (glycogenolysis and glyuconeogenesis)(Berry, Nathan et al. 2009). Glucose levels are controlled by the hormone insulin, and also by the counterregulatory hormones glucagons, cortisol, growth hormone (GH), epinephrine, and norepinephrine. The counterregulatory hormones stimulate production and release of glucose. Hypoglycemia is the most common metabolic problem in

The pituitary gland develops from invagination of the oral ectoderm (Rathke's pouch)(Frohnert and Miller 2009). Nearby neuroectoderm becomes the posterior pituitary, which secretes the hormones oxytocin and vasopressin. Signalling factors involved in the initial differentiation of the anterior pituitary (thickening of the oral ectoderm) include the transcription factors HESX1, PITX1, LHX3, and LHX4. Under the influence of the transcription factor TPIT some of the cells develop into corticotrophs which secrete ACTH. When influenced by transcription factors PROP1, PIT1 (now called POU1F1), PITX1 and PITX2 the remaining cells differentiate into gonadotrophs (which secrete FSH and LH), thyrotrophs (which secrete TSH), somatotrophs (which secrete GH), and lactotrophs (which secrete PRL). During this process the oral ectoderm and the neuroectoderm remain in contact with each other, and both migrate together to form the pituitary with distinct anterior and posterior lobes. All of the hormones of the anterior pituitary are influenced by secretions from the hypothalamus and are regulated through specific feedback loops. Two hormones of the anterior pituitary protect against hypoglycemia— GH and ACTH. ACTH stimulates secretion of cortisol by the adrenal gland. Both GH and cortisol protect against

The GH/IGF axis is shown in Figure 1. It is regulated by three peptides, two from the hypothalamus (that part of the brain closest to the pituitary gland) (Growth Hormone

**1. Introduction** 

neonates, and is also seen in children and adults.

**2. The pituitary-growth hormone-IGF axis** 

hypoglycemia by countering the effects of insulin.

**2.2 The GH-IGF system** 

**2.1 Embryology of the pituitary gland** 

