Glucose is a monosaccharide (aldohexose) and represents the primary energy source for our organism’s cells and the only energy source for central nervous system (CNS) cells and erythrocytes. The circulating glucose comes mainly from the diet, where it is present as monosaccharides and complex carbohydrates (polysaccharides, e.g., starch); a small amount comes from endogenous synthesis (gluconeogenesis). Glucose circulates in free form, and its levels are maintained within a relatively narrow range (70–100 mg/dL) by hormones, such as insulin and glucagon, which ensure that the balance between glucose production and utilization (Fig. 1).

Fig1. Glucose production and utilization. (Copyright EDISES 2021. Reproduced with permission)

In particular, in the postprandial period, most glucose derives from the diet and is metabolized by the body’s cells. Glucose enters cells by facilitated diffusion mediated by glucose transporters (GLUTs), of which there are several iso forms with different characteristics (Table 1). The most important are GLUT-2, acting as a “blood glucose sensor” in pancreatic β-cells that synthesize and secrete insulin, and GLUT-4, which acts on insulin-dependent tissues (the adipose and muscle tissues), and its expression is induced by insulin. Following its entry into a cell, glucose is immediately phosphorylated at glucose-6-P (G-6-P), preventing its escape from the cell (Fig. 2).

Table1. Characteristics of glucose transporters (GLUTs)

Fig2. Glucose phosphorylation reaction. (Copyright EDISES 2021. Reproduced with permission)

This phosphorylation reaction is mediated by hexokinases, of which four isoforms are known, with different characteristics (Table 2).

Table2. Characteristics of hexokinases

In particular, hexokinase IV, also known as glucokinase, is expressed exclusively in the liver and, compared to other hexokinases, it is not inhibited by product (from G-6-P), and, therefore, even in the presence of high glucose concentrations, it mediates phosphorylation. This feature is important because the liver represents the main glucose storage organ.

The postabsorptive period (6–12 h after food ingestion, when the contents of the small intestine have been digested and absorbed) is characterized by a progressive accentuation of hepatic glycogenolysis. During short fasting (e.g., overnight fasting), circulating glucose derives primarily from the liver, by glycogenolysis (glycogen breakdown) and gluconeogenesis (synthesis of glucose from non-saccharide precursors).

During prolonged fasting (> 15 days), circulating glucose derives from the liver and partly from the kidneys, where gluconeogenesis is activated (Fig. 1). After glycogen reserves depletion, free fatty acids from the adipose tissue are mobilized as the liver’s and muscle’s primary source of energy. The brain and anaerobic tissues receive glucose that derives primarily from gluconeogenesis. In addition, hepatic ketone bodies are synthesized from acetyl coenzyme A (acetyl- CoA), released into the circulation and used as an alternative energy source by tissues, including the CNS.

Several hormones are involved in blood glucose regulation (Table 3).

Table3. Characteristics of the hormones involved in blood glucose regulation

Specifically, insulin is a peptide hormone synthesized by pancreatic β-cells, consisting of an α-chain and a β-chain linked by a disulfide bridge. It is synthesized as a preprohormone (signal peptide + proinsulin, formed from insulin + C-peptide) and converted to proinsulin by the signal peptide removal in the endoplasmic reticulum; after S–S bridge formation, proinsulin translocates to the Golgi apparatus, where peptide is removed by proteolytic cutting (Fig. 3).

Fig3. Insulin biosynthesis. (Copyright EDISES 2021. Reproduced with permission)

The mature insulin and C-peptide are stored in secretory granules within β-cells to be released into the circulatory stream by exocytosis in response to an appropriate stimulus. C-peptide is essential for the proper proinsulin folding. Hyperglicemia is the primary stimulus for insulin secretion. Insulin secretion is biphasic, with the first early peak due to secretion of preformed insulin and the second late peak due to ex novo synthesis. Insulin has a short plasma half-life of about 6 min, which determines its rapid circulating concentration variations; 40–60% of the hormone is catabolized in the liver and the remaining amount in the kidneys. The numerous cellular processes regulated by insulin depend on its binding to its receptor located on the membrane of the cells of the target organs, mainly the liver, muscles, and adipose tissue. The receptor is a heterodimer in which the sub units (α and β) are bound by S–S bridges (Fig. 4). Both subunits are extensively glycosylated. The α-subunit is extra cellular and, therefore, it interacts with insulin; the β-subunit consists of a transmembrane and a cytoplasmic portion responsible for signal transduction. The receptor has a half- life of 7–12 h without and 2–3 h with insulin. Insulin is the primary hormone with anabolic and anticatabolic action, promoting the glucose and amino acids uptake by the cells of numerous tissues, stimulating the synthesis of glycogen, fatty acids, and proteins, and inhibiting catabolic processes, such as hormone-sensitive lipase in the adipose tissue and the process of β-oxidation of fatty acids (Fig. 5).

Fig4. Structure of the insulin receptor and insulin mechanism of action. The insulin receptor is a heterodimer, consisting of two extracellular α-chains and two transmembrane β-chains. The α-chains interact with insulin, whereas β-chains mediate intracellular signal transduction. In particular, insulin activates different cellular pathways leading to the GLUT-4 transporter expression on the plasma membrane, the regulation of the activity of different enzymes, and the transcription of insulin-sensitive genes. (Copyright EDISES 2021. Reproduced with permission)

Fig5. Anabolic and anticatabolic effects of insulin. aa, amino acids. (Copyright EDISES 2021. Reproduced with permission)

Glucagon is a protein hormone synthesized by the pancreatic α-cells in response to various stimuli, such as hypoglycemia. It is synthesized as a prehormone, accumulated in secretory vesicles, and is released by exocytosis in response to stimuli. It represents the hormone of energy emergency as it intervenes during substrate deficiency. Glucagon exerts its hyperglycemic action mainly by inducing glycogenolysis (demolition of glycogen) and gluconeogenesis in the liver.

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