Glucose metabolism

Despite periods of feeding and fasting, in normal individuals plasma glucose remains in a narrow range between 4 and 7 mM reflecting the balance between: (i) the release of glucose into the circulation by either absorption from the intestine or the breakdown of stored glycogen in the liver and (ii) the uptake and metabolism of blood glucose by peripheral tissues[1]. These processes are controlled by a set of metabolic hormones. For decades diabetes had been viewed from a bi-hormonal perspective of glucose regulation involving insulin (discovered in the 1920s; released by pancreatic β-cells ) and glucagon (discovered in the 1950s; released by the pancreatic α-cells)[2]. In the mid-1970s several gut hormones, the incretins, were identified. One of these, glucagon-like peptide-1 (GLP-1), was recognized as another important contributor to the maintenance of glucose homeostasis. Subsequently the discovery in 1987, of a second pancreatic β-cell hormone, amylin, whose role complemented that of insulin, led to the view of glucose homeostasis involving multiple hormones[2]. Amylin, like insulin is found to be deficient in people with diabetes. Hormones produced by adipose tissue also play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. These include leptin, adiponectin, acylation stimulating protein and resistin .

Hormones involved

Pancreatic β-cell hormones

Insulin is a key anabolic hormone that is secreted from pancreatic β-cells in response to increased blood glucose and amino acids following ingestion of a meal. Insulin, through its action on the insulin receptor decreases blood sugar levels by: (i) increasing glucose uptake in muscle and fat through triggering the translocation of the intracellular glucose transporter GLUT4 to the plasma membrane (see Insulin-induced glucose transport); (ii) stimulating the storage of glycogen and fat in muscle, liver and adipose tissues through stimulation of the synthesis of glycogen (glycogenesis), fat (lipogenesis) and protein and (iii) reducing glucose production and release by the liver through inhibition of glycogen breakdown (glycogenolysis). Insulin signaling also inhibits the breakdown of fat (lipolysis) and protein.

Amylin is a 37–amino acid neuroendocrine hormone co-expressed and co-secreted with insulin by pancreatic β-cells in response to meals[2]. When secreted by the pancreas, the insulin-to-amylin molar ratio in the portal circulation is approximately 50:1. Because of hepatic extraction of insulin, this ratio falls to ∼ 20:1 in the peripheral circulation[2]. Amylin exerts its actions primarily through the area postrema in the brain stem. It slows down gastric emptying and inhibits digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], resulting in reduction in food intake. Appearance of new glucose in the blood is reduced by inhibiting the secretion of the gluconeogenic hormone glucagon. Thus amylin works with insulin to help coordinate the rate of glucose appearance and disappearance in the circulation with amylin regulating the rate of glucose appearance from both endogenous (liver-derived) and exogenous (meal-derived) sources, and insulin regulating the rate of glucose disappearance[2].

Pancreatic α-cell hormones

Glucagon is a key catabolic hormone secreted by pancreatic α-cells. It opposes the effects of insulin by stimulating hepatic glucose production to sustain plasma glucose levels during fasting conditions. In the diabetic state, there is inadequate suppression of postprandial glucagon secretion (hyperglucagonemia) resulting in elevated hepatic glucose production[2]. Importantly, exogenously administered insulin is unable to restore normal postprandial insulin concentrations in the portal vein nor to suppress glucagon secretion through a paracrine effect. This results in an abnormally high glucagon-to-insulin ratio that favors the release of hepatic glucose. These limits of exogenously administered insulin therapy are well documented in individuals with type 1 or type 2 diabetes and are considered to be important contributors to the postprandial hyperglycemic state characteristic of diabetes[2].

Gut hormones

Incretin hormones are produced by the gut and are released following food ingestion resulting in a more potent release of insulin, than that observed when glucose is infused intravenously. This effect, termed the “incretin effect,” suggested that signals from the gut are important in the hormonal regulation of glucose disappearance. Additionally, these hormonal signals from the proximal gut seemed to help regulate gastric emptying and gut motility. Several incretin hormones have been characterized, and the dominant ones for glucose homeostasis are GIP and GLP-1. GIP stimulates insulin secretion and regulates fat metabolism, but does not inhibit glucagon secretion or gastric emptying[3]. GIP levels are normal or slightly elevated in people with type 2 diabetes[4]. While GIP is a more potent incretin hormone, GLP-1 is secreted in greater concentrations and is more physiologically relevant in humans[3].

Circulating GLP-1 concentrations are low in the fasting state. However, both GIP and GLP-1 are effectively stimulated by ingestion of a mixed meal or meals enriched with fats and carbohydrates. In contrast to GIP, GLP-1 inhibits glucagon secretion and slows gastric emptying[3]. GLP-1 also stimulates glucose-dependent insulin secretion but is significantly reduced postprandially in people with type 2 diabetes or impaired glucose tolerance[4]. GLP-1 stimulates insulin secretion when plasma glucose concentrations are high but not when plasma glucose concentrations approach or fall below the normal range.

Adipocyte hormones

Leptin is a critical peptide hormone involved in the regulation of appetite. It is a protein of 167 amino acids that is expressed, synthesized and secreted by white adipose tissue in proportion to its mass[5]. It can also be produced by brown adipose tissue, ovaries, skeletal muscle, stomach, mammary epithjelial cells, bone marrow, the pituitary and liver[6]. It circulates in blood and acts on the hypothalamus to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This physiological system ensures that total energy stores are stably maintained within a relatively narrow range. The identification of a physiologic system that controls energy balance also establishes a biologic basis for obesity. Leptin also regulates many other physiologic systems and plays a critical role in the adaptive response to starvation[7].

Other metabolic peptides produced by adipocytes include adiponectin, acylation stimulating protein and resistin[8][9][10]. Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues in both humans and animals[8]. Decreased circulating adiponectin levels have been demonstrated in genetic and diet-induced murine models of obesity, as well as in diet-induced forms of human obesity. In humans, plasma levels of adiponectin are significantly lower in insulin-resistant states including type 2 diabetes and can be increased upon administration of the insulin-sensitizing thiazolidinedione (TZD) class of compounds[8].

Acylation stimulating protein (ASP) is a unique hormone produced from complement factor C via an interaction requiring factor B and adipsin (factor D) [9]. ASP acts locally in adipose tissue, where it stimulates glucose uptake, increases the activity of diacylglycerol acyltransferase, and inhibits hormone-sensitive lipase activity. These actions of ASP increase the efficiency of triglyceride synthesis and storage in adipocytes[9].

Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity[10]. Resistin is a member of a class of cysteine-rich proteins collectively termed resistin-like molecules. It has been implicated in the pathogenesis of obesity-mediated insulin resistance and Type II diabetes, at least in rodent models[10]. However there has been considerable controversy surrounding its physiological relevance that has led some to question whether resistin represents an important pathogenic factor in the aetiology of Type II diabetes and cardiovascular disease[10].

Metabolic pathways involved

Glucose transport

Glucose transport into cells is mediated by special proteins termed glucose transporters (GLUT). The human genome contains 14 GLUT genes which exhibit striking tissue-specific expression[11]. The basal glucose transporter is GLUT1 which is present in nearly all cells. It has a Km for glucose of around 1 mM, much less than the average blood glucose concentration of 5-7 mM, enabling most tissues to take up glucose at a fairly constant rate, regardless of the amount present in the blood. Liver (and pancreatic β cells) have a distinct glucose transporter GLUT2 which has a high Km, around 15-20 mM. With these cell types the amount of incoming glucose is proportional to the amount of glucose in the blood. This enables the β cells to monitor blood glucose levels directly, and regulate insulin secretion. It also ensures that glucose is taken up rapidly by the liver only when it is abundant. Muscle and fat cells express a third type of glucose transporter, the insulin-responsive GLUT4, with a Km around 5 mM. The level of this transporter on the surface of these cells is rapidly regulated by insulin[11].

Glycogenolysis and glycogenesis

Glycogenolysis is the biochemical breakdown of glycogen to glucose whereas glycogenesis is the opposite, the formation of glycogen from glucose. Glycogen is a multi-branched polysaccharide of glucose that serves as an energy store primarily in muscle and liver. It is stored in the form of granules in the cytoplasm of the cell and is the main storage form of glucose in the body. Glycogen is an energy reserve that can be quickly mobilized to meet a sudden need for glucose. Glycogenolysis takes place in the cells of muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the adrenaline-induced fight-or-flight response and the regulation of glucose levels in the blood.[12]

Glycogenesis, is the reverse of glycogenolysis and is formation of glycogen from glucose. It occurs in liver and muscle cells when glucose and ATP are present in relatively high amounts.[13] In the synthesis of glycogen, one ATP is required for every glucose unit incorporated into the polymeric branched structure of glycogen. The glucose (in the form of glucose-6-phosphate) is synthesized directly from glucose or as the end product of gluconeogenesis.

Glycolysis and gluconeogenesis

Glycolysis is the enzymatic pathway by which glucose (six carbon sugar) is converted to two molecules of pyruvate (3-carbon sugar). It occurs in the cytoplasm of the cell and does not require the presence of oxygen. The pathway is found (with variations in the terminal steps), in nearly all organisms indicating that it is one of the most ancient known metabolic pathways[14]. In aerobic organisms the pyruvate can be either further metabolized to generate more ATP via the citric acid cycle/cytochrome system, or converted into fatty acids and stored as triglycerides.

Gluconeogenesis is the opposite to glycolysis and is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, citric acid cycle intermediates, amino acids other than lysine or leucine, and glycerol[13]. Transamination or deamination of amino acids facilitates the entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. Gluconeogenesis is one of the two main mechanisms humans and many other animals use to keep blood glucose levels from dropping too low (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis). Gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys. This process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise and is often associated with ketosis.

References

  1. ^ Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001; 414:799-806.

  2. ^ Aronoff SL, et al, Glucose metabolism and regulation: beyond insulin and glucagon, Diabetes Spectr 2004;17:183–190. [http://spectrum.diabetesjournals.org/content/17/3/183.full]

  3. ^ Baggio LL, Drucker DJ, Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131-57.

  4. ^ Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609 –613, 2001

  5. ^ http://en.wikipedia.org/wiki/Leptin

  6. ^ Margetic S, Gazzola C, Pegg GG, Hill RA (2002). "Leptin: a review of its peripheral actions and interactions". Int. J. Obes. Relat. Metab. Disord. 26 (11): 1407–1433.

  7. ^ Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (July 1996). "Role of leptin in the neuroendocrine response to fasting". Nature 382 (6588): 250–2. doi:10.1038/382250a0. PMID 8717038.

  8. ^ Chandran M et al., Adiponectin: More Than Just Another Fat Cell Hormone? Diabetes Care 2003; 26:2442-245

  9. ^ Havel PJ, Update on adipocyte hormones : Regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004; 53:S143-S151

  10. ^ Kusminski CM et al., Role of resistin in obesity, insulin resistance and Type II diabetes. Clin Sci (Lond) 2005; 109:243-56

  11. ^ Scheepers et al., Glucose transporter families SGLT and GLUT: Molecular basis of normal and aberrant function. J Parenteral & Enteral Nutr 2003; 28:364-71

  12. ^ http://en.wikipedia.org/wiki/Glycogenolysis

  13. ^ http://en.wikibooks.org/wiki/Principles_of_Biochemistry/Gluconeogenesis_and_Glycogenesis

  14. ^ http://en.wikipedia.org/wiki/Glycolysis

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