Glucagon is a 29 amino acid (aa) peptide produced by the
pancreas that plays a critical role in glucose metabolism and homeostasis
(1-4). The Glucagon precursor mRNA is expressed by alpha cells ( alpha -cells) of the
pancreas, L cells of the intestine, and in the brain (1, 2). Only the
pancreatic alpha -cells express the prohormone convertase PC2, also called PCSK2,
which is required to produce Glucagon (2). Intestinal L cells instead express
the prohormone convertase PC1, which processes the precursor to the
Glucagon-overlapping peptides glicentin and oxyntomodulin. L cells also produce
two Glucagon-like peptides, GLP-1 and GLP-2 that are derived from the same
Glucagon precursor and influence glucose metabolism, but do not share any
common sequence with Glucagon (1, 2). The aa sequence of the mature Glucagon
peptide is identical in human, mouse, rat, pig, dog, horse, cow, sheep, and
Xenopus.
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
δ-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).