**4.1 Pancreas**

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

During fasting periods, glucose levels in the blood decrease causing inhibition of insulin production in the pancreas by the action of hormones known as catecholamines [4]. Consequently, α-cells in the pancreas are stimulated to produce glucagon hormone that acts antagonistically to insulin. Glucagon makes a function on the different hepatocyte receptors triggering both the action of the phosphorylase enzyme and the glycogenolysis process. Glycogenolysis is the process in which glycogen is converted into glucose to increase blood glucose levels and recover the lack of glucose, setting its concentrations in the desired levels [5]. This is symbol-

*Diabetes Mellitus* is a condition appearing when the glucose homeostasis is broken, that is, plasma glucose levels are no longer maintained at desired levels. This is mainly due to a deficit in the production of insulin from the pancreatic β-cells or

Although some organs need fatty acids to carry out their metabolic processes, most tissues in the human body use glucose as their main source of energy. Good glucose utilization depends on keeping blood glucose levels within range at all times and on the proper functioning of the glucose homeostatic mechanism. Several complementary physiological processes are involved in the glucose homeostatic mechanism. The gastrointestinal tract is responsible to produce and absorb glucose, the liver carries out biochemical reactions such as glycogenolysis, glycolysis, and gluconeogenesis, the kidneys filter, reabsorb, and in some cases excrete glucose,

**124**

**Figure 1.**

ized in **Figure 1** by the minus sign.

*The glucose homeostasis in the human body.*

from a resistance to the action of the produced insulin.

**4. Main organs involved in glucose homeostasis**

The pancreas is a special organ because has both endocrine and exocrine functions. Exocrine functions consist of the production and secretion of digestive enzymes whereas endocrine functions include production and secretion of hormones. This chapter is primarily focused in the endocrine function given the crucial role on glucose homeostasis. Endocrine component of the pancreas consists of clustered cells forming the so-called islets of Langerhans. Islets of Langerhans are small island-shaped structures within exocrine pancreatic tissue representing only 1–2% of the entire organ [6]. The pancreatic islet endocrine cells include five different types that produce and release important hormones directly into the bloodstream: α -cells produce glucagon, β -cells produce amylin-, C-peptide, and insulin [7], γ -cells produce pancreatic polypeptide (PP) [8], δ -cells produce somatostatin [7], and ε -cells produce ghrelin [9]. Two of the pancreatic hormones play an essential role in the regulation of the blood glucose levels are insulin, which acts to lower it, and glucagon, which acts to raise it [10]. The balanced antagonistic action between them, maintain the glucose concentrations within the narrow range of 4–6 *mM* (70 to 110 *mg dL* / ) [6]. However, both hormones are inhibited by somatostatin [11]. Production and secretion of the hormones by pancreatic cells are stimulated by external signals such as nutrients intake, fasting, or stress. Blood glucose levels decrease during periods of rest such as sleep, between meals, or during fasting periods. In these cases, pancreatic α -cells release glucagon to drive glycogenolysis and gluconeogenesis processes. Unlike, in postprandial state, i.e., after a meal ingestion, insulin is released from β -cells in the pancreas to reduce blood glucose levels via glycogenesis [12–14]. Insulin is released on demand but is produced and stored in large, dense-core vesicles that are recruited near the plasma membrane into the β -cells in the islets of Langerhans after stimulation so that insulin is readily available to upcoming stimuli [15]. Glucose is the main signal to release insulin from the pancreas, but free fatty acids and amino acids can increase glucose-induced insulin secretion through the so-called incretin effect. As before mentioned, the incretin effect is originated in the intestinal tract (mainly duodenum) once the food is ingested.

Insulin is a protein made up of 51 amino acids and when produced, it is first synthesized as a single polypeptide known as preproinsulin. Preproinsulin is an insulin gene encoded in 110 amino acids that are then processed into proinsulin. Proinsulin undergoes maturation into active insulin through the action of two different types of cells. One of them cleaves at 2 positions, releasing insulin and a fragment known as C-peptide [16], in an equimolar ratio, into the bloodstream.

Insulin is released from β-cells in the pancreas in two phases, first one is triggered in response to glucose levels and second one is triggered independently of sugar. Glucose and insulin in the bloodstream work together to avoid glucose from going out of range. Thus, Glucose is removed from the circulation thanks to the ability of insulin to cause insulin-dependent tissues to take up glucose [17–19]. Additionally, insulin promotes lipogenesis [20, 21], and the incorporation of amino acids into proteins [22] when it is in high concentrations. Different at low concentrations, which produce lipolysis in adipocytes, releasing free fatty acids by stimulating the use of lipids over glucose to satisfy energy needs at rest [23]. The release of insulin from β-cells is tightly regulated and exactly satisfies the metabolic demand for caloric nutrients in the body [16, 23]. Regarding C-peptide, it has been important to follow some insulin states that are difficult to measure [24].

#### **4.2 Liver**

The liver is perhaps considered the main blood glucose regulating organ in the human body because it functions in two different ways: controlling the rate of glucose absorption from the portal system and producing glucose from non-carbohydrate precursors or glycogen. As a curious fact, the liver is the only organ being irrigated by venous and arterial blood simultaneously. Venous irrigation comes from the portal system, provides the 75% of the blood supply, and carries blood rich in nutrients that were absorbed from the small intestine through enterocytes and hormones that were released by the pancreas. On the other hand, 25% of the remaining hepatic blood supply is arterial supply and is oxygen-rich blood coming from the aorta [4]. Blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules is emptied into low-pressure vascular channels called sinusoids. Sinusoids are lined with endothelial cells and flanked circumferentially by plates of parenchymal cells-hepatocytes allowing the exchange of nutrients and oxygen between the blood and the hepatic cells [25]. Millions of sinusoids made up the lobules in the liver. Hepatocytes take up nutrients from blood in the sinusoid and once carry on all metabolic functions, return the substances resulting from the biochemical reactions to the blood via hepatic vein.

As mentioned earlier, the liver is a key organ in maintaining glucose concentrations in the desired range over both post-absorptive and postprandial states1 . In the liver, four biochemical processes regarding glucose metabolism take place: glucose production from glycogen (glycogenolysis) and from non-carbohydrate precursors (gluconeogenesis), glucose consumption during the postprandial state (glucolysis), and glucose storage from the formation of glycogen (glycogenesis). Glucose phosphorylation (formation of glycogen) and dephosphorylation (formation of glucose from glycogen) occurs through the action of insulin and glucagon, respectively. Hepatocytes express dozens of enzymes that alternately turn on and off depending on whether blood glucose levels are rising or falling outside the normal range [26]. In the post-absorptive state, the human body is under fasting and the body must rely initially on stored glycogen to supply with glucose to the central nervous system and simultaneously regulate plasma glucose concentrations. If the fast is prolonged, the glycogen stores end, and the glucose dosage in the liver depends only on gluconeogenesis. On the other hand, after an ingested meal, i.e., in the postprandial state, absorbed nutrients enter the liver first from hepatic portal vein. Consequently, glycogen concentrations in the hepatocytes are restored by taking up a portion of the ingested glucose, minimizing the fluctuations of glycemia. In this case, gluconeogenesis is also occurring at a constant rate but the glucose output generated from glycogenolysis is suppressed. These result in a net switch from hepatic glucose output to hepatic glucose uptake [27].

Hepatic gluconeogenesis occurs by the action of additional groups of enzymes that are activated to start synthesizing glucose out of such precursors as amino acids and non-hexose carbohydrates such as glutamine, alanine, lactate and glycerol. Otherwise, the suppression of the glycogenolysis during the post-absorptive period and the activation of the glycogen synthesis during the postprandial period are mainly driven by stimulation of insulin secretion and suppression of glucagon secretion.

**127**

also occur within the renal tubules [5].

*Main Organs Involved in Glucose Metabolism DOI: http://dx.doi.org/10.5772/intechopen.94585*

reenters the circulation [34].

**4.3 Kidneys**

is the synthesis of excess glucose into fatty acids [36].

In addition to being the primary site of glucose utilization during the postprandial period and glucose dosing during the post-absorption period, the liver is the primary site of clearance of insulin in the human body [28, 29]. Although the kidneys are the main site of extrasplanchnic insulin clearance, with additional contributions resulting from uptake and degradation by peripheral insulin-sensitive tissues, i.e., skeletal muscle and adipose tissue, the liver is the main organ responsible for clearance of exogenous and in particular endogenous insulin [30]. Insulin clearance from the liver is a dynamic process that can be modified within a few days under conditions of changing energy and, in particular, carbohydrate intake and before major changes in basal insulin secretion [31]. However, during first-pass transit near to 50% of the portal insulin is removed in the liver [32]. Removal of insulin from circulation does not imply the immediate destruction of the hormone [33]. A significant amount of receptor-bound insulin is released from the cell and

Hepatic glucose uptake is maximally stimulated by conditions that mimic the postprandial state, such as portal venous hyperglycemia and hyperinsulinemia [35]. Once glucose reaches the hepatocytes, it is phosphorylated to glucose 6-phosphate to synthesize glycogen, among other metabolic pathways. The ability of the liver to store glycogen is limited, and when glycogen concentrations reach maximum capacity, the hepatocytes initiate a process known as lipogenesis. Lipogenesis

In conclusion, during short periods of fasting, glycogenolysis is the predominant source of glucose released into the bloodstream. However, during prolonged periods of fasting, the glycogen store is gradually depleted and glycogenolysis decreases as glycogen stores are depleted. So, gluconeogenesis becomes the predominant source of glucose for the human body. This unique ability of the human

The kidneys are two bean-shaped organs that are primarily engaged in filtering the blood and excreting waste. Filtration is about cleaning the blood to send it back into circulation, maintaining an overall fluid balance, creating hormones that help make red blood cells, promoting bone health, and regulating blood pressure [37]. Recent studies have demonstrated that kidneys also play a central role in glucose homeostasis through utilization of glucose, glucose production, and glucose filtration and reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters (GLUT-2). Moreover, the kidneys are an important site of insulin clearance from the systemic circulation, removing approximately 50% of peripheral insulin [34]. The kidneys have a super-specialized microscopic structural and functional unit called the nephron. Nephrons have the ability to distribute all functions in each of their parts. For example, the glomerulus is a network of small blood vessels known as capillaries located within Bowman's capsule. Blood is filtered across the glomerular capillaries into Bowman's space. These capillaries are multiple branches of the afferent arteriole but then converge at the efferent arteriole to exit the glomerulus and surround the renal tubules, including the proximal convoluted tubule, the proximal rectus tubule, the loop of Henle, the distal convoluted tubule, and the collecting ducts. Urine continually forms within the tubules to be excreted with waste products. Reabsorption, secretion, chemical reactions, and excretion

The release of glucose occurs predominantly in the renal cortex, while the utilization of glucose is limited to the renal medulla. For this reason, the kidneys

liver to store and release glucose is crucial to supporting periods of fasting.

<sup>1</sup> Postprandial state is the time frame after a meal or food intake. Postabsorptive state is the period following absorption of nutrients from the digestive tract, that is, is the time when enterocytes stop providing nutrients to the hepatic portal circulation. Fasting is the willing abstinence or reduction from some or all food, drink, or both, for a long period of time (˷ 8 hours).

#### *Main Organs Involved in Glucose Metabolism DOI: http://dx.doi.org/10.5772/intechopen.94585*

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

biochemical reactions to the blood via hepatic vein.

from hepatic glucose output to hepatic glucose uptake [27].

suppression of glucagon secretion.

some or all food, drink, or both, for a long period of time (˷

Hepatic gluconeogenesis occurs by the action of additional groups of enzymes that are activated to start synthesizing glucose out of such precursors as amino acids and non-hexose carbohydrates such as glutamine, alanine, lactate and glycerol. Otherwise, the suppression of the glycogenolysis during the post-absorptive period and the activation of the glycogen synthesis during the postprandial period are mainly driven by stimulation of insulin secretion and

<sup>1</sup> Postprandial state is the time frame after a meal or food intake. Postabsorptive state is the period following absorption of nutrients from the digestive tract, that is, is the time when enterocytes stop providing nutrients to the hepatic portal circulation. Fasting is the willing abstinence or reduction from

8 hours).

The liver is perhaps considered the main blood glucose regulating organ in the human body because it functions in two different ways: controlling the rate of glucose absorption from the portal system and producing glucose from non-carbohydrate precursors or glycogen. As a curious fact, the liver is the only organ being irrigated by venous and arterial blood simultaneously. Venous irrigation comes from the portal system, provides the 75% of the blood supply, and carries blood rich in nutrients that were absorbed from the small intestine through enterocytes and hormones that were released by the pancreas. On the other hand, 25% of the remaining hepatic blood supply is arterial supply and is oxygen-rich blood coming from the aorta [4]. Blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules is emptied into low-pressure vascular channels called sinusoids. Sinusoids are lined with endothelial cells and flanked circumferentially by plates of parenchymal cells-hepatocytes allowing the exchange of nutrients and oxygen between the blood and the hepatic cells [25]. Millions of sinusoids made up the lobules in the liver. Hepatocytes take up nutrients from blood in the sinusoid and once carry on all metabolic functions, return the substances resulting from the

As mentioned earlier, the liver is a key organ in maintaining glucose concentra-

. In

tions in the desired range over both post-absorptive and postprandial states1

the liver, four biochemical processes regarding glucose metabolism take place: glucose production from glycogen (glycogenolysis) and from non-carbohydrate precursors (gluconeogenesis), glucose consumption during the postprandial state (glucolysis), and glucose storage from the formation of glycogen (glycogenesis). Glucose phosphorylation (formation of glycogen) and dephosphorylation (formation of glucose from glycogen) occurs through the action of insulin and glucagon, respectively. Hepatocytes express dozens of enzymes that alternately turn on and off depending on whether blood glucose levels are rising or falling outside the normal range [26]. In the post-absorptive state, the human body is under fasting and the body must rely initially on stored glycogen to supply with glucose to the central nervous system and simultaneously regulate plasma glucose concentrations. If the fast is prolonged, the glycogen stores end, and the glucose dosage in the liver depends only on gluconeogenesis. On the other hand, after an ingested meal, i.e., in the postprandial state, absorbed nutrients enter the liver first from hepatic portal vein. Consequently, glycogen concentrations in the hepatocytes are restored by taking up a portion of the ingested glucose, minimizing the fluctuations of glycemia. In this case, gluconeogenesis is also occurring at a constant rate but the glucose output generated from glycogenolysis is suppressed. These result in a net switch

**4.2 Liver**

**126**

In addition to being the primary site of glucose utilization during the postprandial period and glucose dosing during the post-absorption period, the liver is the primary site of clearance of insulin in the human body [28, 29]. Although the kidneys are the main site of extrasplanchnic insulin clearance, with additional contributions resulting from uptake and degradation by peripheral insulin-sensitive tissues, i.e., skeletal muscle and adipose tissue, the liver is the main organ responsible for clearance of exogenous and in particular endogenous insulin [30]. Insulin clearance from the liver is a dynamic process that can be modified within a few days under conditions of changing energy and, in particular, carbohydrate intake and before major changes in basal insulin secretion [31]. However, during first-pass transit near to 50% of the portal insulin is removed in the liver [32]. Removal of insulin from circulation does not imply the immediate destruction of the hormone [33]. A significant amount of receptor-bound insulin is released from the cell and reenters the circulation [34].

Hepatic glucose uptake is maximally stimulated by conditions that mimic the postprandial state, such as portal venous hyperglycemia and hyperinsulinemia [35]. Once glucose reaches the hepatocytes, it is phosphorylated to glucose 6-phosphate to synthesize glycogen, among other metabolic pathways. The ability of the liver to store glycogen is limited, and when glycogen concentrations reach maximum capacity, the hepatocytes initiate a process known as lipogenesis. Lipogenesis is the synthesis of excess glucose into fatty acids [36].

In conclusion, during short periods of fasting, glycogenolysis is the predominant source of glucose released into the bloodstream. However, during prolonged periods of fasting, the glycogen store is gradually depleted and glycogenolysis decreases as glycogen stores are depleted. So, gluconeogenesis becomes the predominant source of glucose for the human body. This unique ability of the human liver to store and release glucose is crucial to supporting periods of fasting.

#### **4.3 Kidneys**

The kidneys are two bean-shaped organs that are primarily engaged in filtering the blood and excreting waste. Filtration is about cleaning the blood to send it back into circulation, maintaining an overall fluid balance, creating hormones that help make red blood cells, promoting bone health, and regulating blood pressure [37]. Recent studies have demonstrated that kidneys also play a central role in glucose homeostasis through utilization of glucose, glucose production, and glucose filtration and reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters (GLUT-2). Moreover, the kidneys are an important site of insulin clearance from the systemic circulation, removing approximately 50% of peripheral insulin [34].

The kidneys have a super-specialized microscopic structural and functional unit called the nephron. Nephrons have the ability to distribute all functions in each of their parts. For example, the glomerulus is a network of small blood vessels known as capillaries located within Bowman's capsule. Blood is filtered across the glomerular capillaries into Bowman's space. These capillaries are multiple branches of the afferent arteriole but then converge at the efferent arteriole to exit the glomerulus and surround the renal tubules, including the proximal convoluted tubule, the proximal rectus tubule, the loop of Henle, the distal convoluted tubule, and the collecting ducts. Urine continually forms within the tubules to be excreted with waste products. Reabsorption, secretion, chemical reactions, and excretion also occur within the renal tubules [5].

The release of glucose occurs predominantly in the renal cortex, while the utilization of glucose is limited to the renal medulla. For this reason, the kidneys can be considered as two separate organs [38–42]. The renal medulla has an appreciable glucose phosphorylation capacity and, therefore, the ability to accumulate glycogen [42]. However, the kidney medulla consumes glucose anaerobically due to its low oxygen tension and low levels of oxidative enzymes, limiting the ability to produce glucose from glycogen. Consequently, lactate is the main metabolic end product of glucose taken up at the renal medulla, unlike carbon dioxide (*CO*<sup>2</sup> ) and water that are the end products of glucose uptake of aerobic energy requirements. In contrast, the renal cortex does not have appreciable glycogen stores [43] because has little glucose phosphorylation capacity but has a high level of oxidative enzymes like 6-phosphatase. Consequently, this part of the kidney does not take up and use much glucose, with oxidation of free fatty acids acting as the main source of energy [44]. Therefore, it is likely that glucose release by the normal kidney is primarily due to gluconeogenesis, that is, the synthesis of glucose-6-phosphate from non-carbohydrate precursors such as glutamine, lactate, alanine, glycerol, etc. [45], being glutamine the substrate with more specificity in the kidney but lactate the most abundant.

In addition, to its function both in the use and in the production of glucose, the kidneys contribute to the regulation of glucose in the blood by filtering and reabsorbing glucose. The glomeruli filter glucose once it reaches the kidneys, with other substances such as precursors and insulin, into the proximal tubules, where all the glucose is reabsorbed through the glucose transporting proteins present in the cell membranes within the proximal tubules [46], rendering the urine virtually glucose free. Before being reabsorbed, gluconeogenesis and glucose uptake occur. Glucose production is suppressed by insulin [45] or stimulated by non-carbohydrate precursors [41, 47]. An interesting fact is that GLUT-2 glucose transporters are independent of insulin and for that reason, the kidneys can continue their physiological functions even in states of insulin deficiency [23].

As before mentioned, gluconeogenesis in the human body is mainly carried out by the liver and the kidneys. In the post-absorptive state, both liver and kidneys release glucose into the circulation in comparable amounts [48]. However, in the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twice liver gluconeogenesis. In this sense, the hepatic and renal glucose release into the circulation in the post-absorptive state correspond to the 25–30% and 20–25% of total glucose, respectively, while in postprandial state, hepatic gluconeogenesis is reduced by ∼ 80% and the release of glucose molecules generated via this pathway decreases as these molecules are largely directed into the formation of hepatic glycogen. As a consequence of these changes, renal gluconeogenesis increases accounts for ∼ 60% of postprandial endogenous glucose release [49].

#### **4.4 Gastrointestinal tract**

The gastrointestinal (GI) tract is an organ system, consisting of the mouth, esophagus, stomach, and intestines, where humans ingest food, digest it to extract and absorb energy and nutrients, and expel the remaining waste as feces. However, the literature on glucose homeostasis includes the gastrointestinal tract as a complete organ without taking into account the physiological functions and glucose consumption of the stomach and small intestine as separate organs involved in glucose metabolism.

Meal is ingested through mouth and enters in the stomach to be mixed. The rate at which nutrients pass from the stomach to the duodenum, i.e., crossing the pyloric valve, is known as the gastric emptying rate and is a key determinant of

**129**

brain diseases.

*Main Organs Involved in Glucose Metabolism DOI: http://dx.doi.org/10.5772/intechopen.94585*

tory hormones of glucose including amylin from

appropriate tissue stores [52–54].

glucose in the bloodstream.

**4.5 Brain**

postprandial glucose flow. In the fed state, glucose homeostasis becomes more complex as the gastrointestinal tract becomes a second source of exogenous glucose. Marked and rapid changes in glucose flux occur as a result of the considerable inflow of meal-derived glucose into the circulation [50]. The delivery of nutrients from the gastrointestinal tract occurs through an important rate limiting mechanical step in the form of gastric emptying rate: the rate at which the pylorus allows small boluses of gastric content to pass into the duodenum for downstream absorption. Importantly, neither insulin nor glucagon has direct effects on gastric emptying and exogenous glucose diffusion from the gastrointestinal tract [51]. However, the influx of glucose is accompanied by secretion of several other regula-

glucose-dependent inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK) from endocrine cells in the small intestine. Endocrine cells in the small intestine collectively influence glucose homeostasis via several mechanisms of action including regulation of insulin and glucagon responses, as well as the modulation of nutrient passage from the gastrointestinal tract to

A key contribution of the GI tract on glucose homeostasis is the incretin effect. This physiological response came from the observation that an oral glucose load results in an increased insulin response compared to the response seen when intravenous glucose administration replicates the same changes in plasma glucose

response is observed as a result of a signal passed from the gut. The two hormones responsible for this effect are GIP and GLP-1. Both GIP, secreted from enteroendocrine K-cells in the proximal small bowel, and GLP-1, secreted from enteroendocrine L-cells in the distal ileum and colon, have a strong insulinotropic effect [57]. Additionally, GLP-1 inhibits postprandial glucagon secretion in a glucosedependent manner, slows gastric emptying, and reduces food intake, contributing to postprandial glucose regulation [58]. Regarding the role of the stomach in the metabolism of glucose, the stomach must consume glucose to generate the energy necessary to mechanically carry out the digestion process. Although the consumption of glucose in the stomach is relatively low, it can affect the concentration of

The human brain depends on glucose as its main source of energy; neurons have the highest energy demand [59] of all types of cells in the human body, requiring continuous delivery of glucose from blood. Glucose metabolism provides the fuel for physiological brain function through the generation of ATP, the foundation for neuronal and non-neuronal cellular maintenance, as well as the generation of neurotransmittersTherefore, tight regulation of glucose metabolism is critical to brain physiology. In this sense, the alteration of glucose metabolism in the brain is the basis of several diseases that affect both the brain and the entire organism. Glucose is required in the brain to provide the precursors of neurotransmitter synthesis and ATP to fuel their actions. Additionally, glucose is important for the brain's energy demands unrelated to signaling. Cellular compartmentalization of glucose transport and metabolism are closely related to local regulation of blood flow, and glucose-sensing neurons govern the brain–body nutrient axis. Glucose metabolism is connected to cell death pathways by the glucose-metabolizing enzymes [60]. Thus, disruption glucose delivery pathways and metabolism leads to debilitating

[55, 56]. In other words, when glucose is ingested orally, an augmented

β


β-cell

#### *Main Organs Involved in Glucose Metabolism DOI: http://dx.doi.org/10.5772/intechopen.94585*

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

kidney but lactate the most abundant.

ological functions even in states of insulin deficiency [23].

of postprandial endogenous glucose release [49].

**4.4 Gastrointestinal tract**

glucose metabolism.

can be considered as two separate organs [38–42]. The renal medulla has an appreciable glucose phosphorylation capacity and, therefore, the ability to accumulate glycogen [42]. However, the kidney medulla consumes glucose anaerobically due to its low oxygen tension and low levels of oxidative enzymes, limiting the ability to produce glucose from glycogen. Consequently, lactate is the main metabolic end product of glucose taken up at the renal medulla, unlike carbon dioxide (*CO*<sup>2</sup> ) and water that are the end products of glucose uptake of aerobic energy requirements. In contrast, the renal cortex does not have appreciable glycogen stores [43] because

has little glucose phosphorylation capacity but has a high level of oxidative enzymes like 6-phosphatase. Consequently, this part of the kidney does not take up and use much glucose, with oxidation of free fatty acids acting as the main source of energy [44]. Therefore, it is likely that glucose release by the normal kidney is primarily due to gluconeogenesis, that is, the synthesis of glucose-6-phosphate from non-carbohydrate precursors such as glutamine, lactate, alanine, glycerol, etc. [45], being glutamine the substrate with more specificity in the

In addition, to its function both in the use and in the production of glucose, the kidneys contribute to the regulation of glucose in the blood by filtering and reabsorbing glucose. The glomeruli filter glucose once it reaches the kidneys, with other substances such as precursors and insulin, into the proximal tubules, where all the glucose is reabsorbed through the glucose transporting proteins present in the cell membranes within the proximal tubules [46], rendering the urine virtually glucose free. Before being reabsorbed, gluconeogenesis and glucose uptake occur. Glucose production is suppressed by insulin [45] or stimulated by non-carbohydrate precursors [41, 47]. An interesting fact is that GLUT-2 glucose transporters are independent of insulin and for that reason, the kidneys can continue their physi-

As before mentioned, gluconeogenesis in the human body is mainly carried out by the liver and the kidneys. In the post-absorptive state, both liver and kidneys release glucose into the circulation in comparable amounts [48]. However, in the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twice liver gluconeogenesis. In this sense, the hepatic and renal glucose release into the circulation in the post-absorptive state correspond to the 25–30% and 20–25% of total glucose, respectively, while in postprandial state, hepatic gluconeogenesis is reduced by ∼ 80% and the release of glucose molecules generated via this pathway decreases as these molecules are largely directed into the formation of hepatic glycogen. As a consequence of these changes, renal gluconeogenesis increases accounts for ∼ 60%

The gastrointestinal (GI) tract is an organ system, consisting of the mouth, esophagus, stomach, and intestines, where humans ingest food, digest it to extract and absorb energy and nutrients, and expel the remaining waste as feces. However, the literature on glucose homeostasis includes the gastrointestinal tract as a complete organ without taking into account the physiological functions and glucose consumption of the stomach and small intestine as separate organs involved in

Meal is ingested through mouth and enters in the stomach to be mixed. The rate

at which nutrients pass from the stomach to the duodenum, i.e., crossing the pyloric valve, is known as the gastric emptying rate and is a key determinant of

**128**

postprandial glucose flow. In the fed state, glucose homeostasis becomes more complex as the gastrointestinal tract becomes a second source of exogenous glucose. Marked and rapid changes in glucose flux occur as a result of the considerable inflow of meal-derived glucose into the circulation [50]. The delivery of nutrients from the gastrointestinal tract occurs through an important rate limiting mechanical step in the form of gastric emptying rate: the rate at which the pylorus allows small boluses of gastric content to pass into the duodenum for downstream absorption. Importantly, neither insulin nor glucagon has direct effects on gastric emptying and exogenous glucose diffusion from the gastrointestinal tract [51]. However, the influx of glucose is accompanied by secretion of several other regulatory hormones of glucose including amylin from β -cells in the pancreas and glucose-dependent inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK) from endocrine cells in the small intestine. Endocrine cells in the small intestine collectively influence glucose homeostasis via several mechanisms of action including regulation of insulin and glucagon responses, as well as the modulation of nutrient passage from the gastrointestinal tract to appropriate tissue stores [52–54].

A key contribution of the GI tract on glucose homeostasis is the incretin effect. This physiological response came from the observation that an oral glucose load results in an increased insulin response compared to the response seen when intravenous glucose administration replicates the same changes in plasma glucose [55, 56]. In other words, when glucose is ingested orally, an augmented β -cell response is observed as a result of a signal passed from the gut. The two hormones responsible for this effect are GIP and GLP-1. Both GIP, secreted from enteroendocrine K-cells in the proximal small bowel, and GLP-1, secreted from enteroendocrine L-cells in the distal ileum and colon, have a strong insulinotropic effect [57]. Additionally, GLP-1 inhibits postprandial glucagon secretion in a glucosedependent manner, slows gastric emptying, and reduces food intake, contributing to postprandial glucose regulation [58]. Regarding the role of the stomach in the metabolism of glucose, the stomach must consume glucose to generate the energy necessary to mechanically carry out the digestion process. Although the consumption of glucose in the stomach is relatively low, it can affect the concentration of glucose in the bloodstream.

#### **4.5 Brain**

The human brain depends on glucose as its main source of energy; neurons have the highest energy demand [59] of all types of cells in the human body, requiring continuous delivery of glucose from blood. Glucose metabolism provides the fuel for physiological brain function through the generation of ATP, the foundation for neuronal and non-neuronal cellular maintenance, as well as the generation of neurotransmittersTherefore, tight regulation of glucose metabolism is critical to brain physiology. In this sense, the alteration of glucose metabolism in the brain is the basis of several diseases that affect both the brain and the entire organism. Glucose is required in the brain to provide the precursors of neurotransmitter synthesis and ATP to fuel their actions. Additionally, glucose is important for the brain's energy demands unrelated to signaling. Cellular compartmentalization of glucose transport and metabolism are closely related to local regulation of blood flow, and glucose-sensing neurons govern the brain–body nutrient axis. Glucose metabolism is connected to cell death pathways by the glucose-metabolizing enzymes [60]. Thus, disruption glucose delivery pathways and metabolism leads to debilitating brain diseases.

The brain uses about 120 g of glucose per day - 60-70% of the body's total glucose metabolism. The brain has little stored glucose and has no additional sources of stored energy. Brain function begins to become seriously affected when glucose levels fall below ~ 40 / *mg dL*. Glucose levels significantly below this can lead to permanent damage and death. The brain cannot use fatty acids for energy (fatty acids do not cross the blood–brain barrier of the neurons), but ketone bodies can enter the brain and be used for energy in hypoglycemic conditions. In this sense, the brain can only use glucose, or, under conditions of starvation, ketone bodies (acetoacetate and hydroxybutyrate) for energy.
