Glucagon Glucagonic Fitness Glucose Cure

Glucagon Glucagonic Fitness Glucose Cure

Glucagon is an important hormone involved in carbohydrate metabolism. Produced by the pancreas, it is released when the glucose level in the blood is low (HYPOglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin, which instructs the body's cells to take in glucose from the blood in times of satiation.

Production

The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet.

Regulatory mechanism

Increased secretion of glucagon is caused by:

* Decreased plasma glucose
* Increased catecholamines - norepinephrine and epinephrine
* Increased plasma amino acids (to protect from hypoglycemia if an all protein meal is consumed)
* Sympathetic nervous system
* Acetylcholine
* Cholecystokinin

Decreased secretion of glucagon (inhibition) is caused by:

* Somatostatin
* Insulin

Function

Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia. Glucagon also regulates the rate of glucose production through lipolysis.

* Increased free fatty acids and ketoacids into the blood
* Increased urea production

Mechanism of action

Glucagon binds to the glucagon receptor, a G protein-coupled receptor located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. The subunits breakup as a result of substitution of a GDP molecule with a GTP mol, and the alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cAMP (cyclical AMP) which activates protein kinase A (cAMP-dependent protein kinase). This enzyme in turn activates phosphorylase kinase, which in turn, phosphorylates glycogen phosphorylase, converting into the active form called phosphorylase A. Phosphorylase A is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

Endocrinology. 1996 Aug;137(8):3193-9.

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Glucagon response to HYPOglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats.

Shi ZQ, Rastogi KS, Lekas M, Efendic S, Drucker DJ, Vranic M.

Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.

The aim of this study was to determine whether the impaired glucagon response to insulin-induced hypoglycemia in the diabetic rat can be improved by correction of hyperglycemia independent of insulin.

Four groups of age-matched male Sprague-Dawley rats (246 +/- 13 g BW) were studied: 1) normal controls (NC; n = 7); 2) diabetic, untreated (DU; n = 6); 3) diabetic, treated for 5-7 days using sustained release (2-3 U/day) insulin implants (DI; n = 6); and 4) diabetic, treated for 3-4 days with phlorizin (0.4 g/kg), given sc twice daily (DP; n = 7). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). Basal plasma glucose was 7.4 +/- 0.3 mM in NC, but rose to 14.5 +/- 2.2 mM in DU.

Basal hyperglycemia was corrected with phlorizin and insulin treatments (5.5 +/- 0.5 and 6.7 +/- 0.8 mM, respectively). NC rats responded to insulin-induced hypoglycemia with a rapid and marked increase in glucagon (peak, 2059 +/- 311 pg/ml). The glucagon response was blunted in DU (635 +/- 180 pg/ml) and was partially improved by prolonged normalization of glycemia in DP (1335 +/- 295 pg/ml; P <>

Treatment with both insulin and phlorizin reversed the changes in the pancreatic content of both glucagon and somatostatin. Pancreatic proglucagon messenger RNA did not show significant differences among the four groups in either state. Insulin treatment in the DI group resulted in a delayed and much smaller increase in the glucagon response (740 +/- 138 pg/ml) to hypoglycemia despite normalization of glycemia.

We, therefore, conclude that in streptozotocin-diabetic rats, the impaired glucagon responsiveness to hypoglycemia is significantly improved by insulin-independent correction of hyperglycemia, suggesting the importance of normoglycemia per se in maintaining, at least in part, the glucose sensitivity of pancreatic alpha-cells.

Endocrinology. 1998 Nov;139(11):4540-6.

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Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes.

Dumonteil E, Magnan C, Ritz-Laser B, Meda P, Dussoix P, Gilbert M, Ktorza A, Philippe J.

Department of Medicine, Centre Médical Universitaire, Geneva, Switzerland.

The factors that regulate glucagon biosynthesis and proglucagon gene expression are poorly defined. We previously reported that insulin inhibits proglucagon gene expression in vitro.

In vivo, however, the effects of insulin on the regulation of the proglucagon gene have been controversial. Furthermore, whether glucose plays any role alone or in conjunction with insulin on proglucagon gene expression is unknown.

We investigated the consequences of insulinopenic diabetes on glucagon gene expression in the endocrine pancreas and intestine and whether insulin and/or glucose could correct the observed abnormalities.

We show here that in the first 3 days after induction of hyperglycemia by streptozotocin, rats have levels of plasma glucagon and proglucagon messenger RNA comparable to those of normoglycemic controls despite hyperglycemia.

With more prolonged diabetes, plasma glucagon and proglucagon messenger RNA levels increase; this increase is corrected by insulin treatment, but not by phloridzin despite normalization of the glycemia by both treatments.

Proglucagon gene expression exhibits the same regulatory response to glucose and insulin in both pancreas and ileum.

We conclude that insulin tonically inhibits proglucagon gene expression in the pancreas and ileum and that glucose plays a minor, if any, role in this regulation.