In normal metabolism, Glucagon is secreted in response to low blood glucose (hypoglycemia) and downregulated in response to high blood glucose (hyperglycemia). Although Glucagon binding sites are found in liver, brain, pancreas, kidney, intestine, and adipose tissue, the main activity of Glucagon receptors occurs in the liver, where Glucagon stimulates gluconeogenesis and glycogenolysis, thereby increasing blood glucose (1-4). It is particularly important that the brain receive sufficient glucose, since it is unable to store more than a minute quantity. Therefore the release of Glucagon from alpha -cells is under control by both hormones and neurotransmitters, and is very responsive to circulating glucose concentration. Insulin, and/or the zinc that islet beta cells secrete with it, downregulates Glucagon secretion in intact islets (5, 6). Glucagon secretion is also downregulated by the neurotransmitter gamma -aminobutyric acid (GABA), somatostatin produced by islet delta -cells, and GLP-1, but is enhanced by the neurotransmitter L-glutamate, amino acids (especially arginine), and Glucagon itself (2-4, 7). Through receptors on the alpha -cells, these substances affect potassium, sodium, and calcium channel activity and alter intracellular calcium concentration (2-4). Glucose suppression of Glucagon secretion is probably indirect, acting through paracrine signals from other islet cells (8).
Like insulin, Glucagon is dysregulated in type 2 diabetes (T2D) and contributes to its pathology (2-4). Glucagon secretion is less responsive to insulin-mediated suppression in times of high circulating glucose, causing glucagonemia, and increasing the risk of hyperglycemia. Glucagon is also regulated by some of the same messengers that regulate insulin (10-12). Leptin inhibits alpha -cell glucagon secretion and stimulates beta -cell insulin secretion, but glucagon blunts the leptin-mediated insulin secretion (10). Islet alpha -cells express ghrelin receptors and respond to ghrelin by increasing Glucagon secretion (11). Glucocorticoids, activated by 11 beta -HSD1, depress Glucagon secretion in hypoglycemia and insulin secretion in hyperglycemia (12). Although genetic polymorphisms of the Glucagon receptor are associated with T2D, downregulation of Glucagon secretion or deletion of the Glucagon receptor in mice that are susceptible to T2D actually improves glycemic control (13, 14).
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