Glucagon’s stimulation of hepatic gluconeogenesis and glycogenolysis is essential to the liver’s maintenance of proper blood concentrations of glucose. Also in adipocytes, glucagon acting through its receptor stimulates lipolysis which converts stored triglycerides into free fatty acids as a substrate for subsequent con version to glucose.

Glucagon and the glucagon-like peptides are all produced from a single proglucagon gene; see Figure 1. In the pancreas only glucagon is expressed and secreted. The secretion of glucagon is strictly regulated by an array of agents. Examples of agonists include neuropeptides, hormones (epinephrine), and amino acids (arginine, glutamine, and alanine). Antagonists of glucagon secretion include glucose and somatostatin.

Fig1. Schematic diagram of the proglucagon domain organization in the pancreas and intestine and secretion products from the pancreas (glucagon) and small intestine (GLP-1, GLP-2, and oxyntomodulin peptides). In the pancreas, the secretion of glucagon is strictly regulated by an array of agents. Examples of agonists include neuropeptides, hormones (epinephrine), and amino acids (arginine, glutamine, and alanine). Antagonists of glucagon secretion include glucose and somatostatin. In contrast, in the intestine both glucagon-like peptides (GLP-1 and GLP-2) are secreted by the intestinal L cell. GLP-1 is a potent antihyperglycemic hormone, with a half-life of only 2 minutes, that stimulates glucose-dependent insulin secretion while suppressing glucagon secretion. The actions of GLP-2 are less clear. In the pancreas, proglucagon is processed to secrete intact full-length glucagon (29 amino acids). The “major” proglucagon fragment (amino acid residues 72–158) has no known biological functions. In contrast, in the intestine, proglucagon is designed to secrete (i) oxyntomodulin, a 37 amino acid peptide that contains the 29 amino acid sequence of glucagon followed by an 8 amino acid carboxy-terminal, (ii) glucagon-like peptide-1 (GLP-1), and (iii) glucagon-like-peptide-2 (GLP-2). There is also some information suggesting that the intestinal oxyntomodulin displays weak affinity for the glucagon receptor and may mimic glucagon actions in the pancreas and liver. Portions of this figure came from G.I. Bell et al. Nature B304:368–371 (1983) and J Nutrition, 133: 3709–3711 (2003). The amino acid sequences came with permission from DeGroot, Endocrinology, ch. 35, page 661 (2010).

The proglucagon gene is expressed in the gastro intestinal tract in the stomach and both the small and large intestine; see Figure 1. It gives rise to several peptides that individually play diverse roles in the control of energy intake and storage, intestinal motility, and nutrient disposal. Oxyntomodulin (OXY) is derived from the proglucagon gene.

It has a 37-amino-acid peptide that includes on its N-terminus the 29-amino-acid sequence of glucagon followed by an 8-amino- acid peptide on its car boxyterminal extension, glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide that participates in the modulation of glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. GLP-1 generates a sensation of increased satiety and likely diminishes appetite via central effects on the regions of the hypo thalamus. At times of food intake, GLP-2 is simultaneously secreted with GLP-1 from intestinal endocrine cells. GLP-2 is trophic to the intestinal tract in both the small and large intestine. The biological activities of glucagon-like peptides, GLP-1 and GLP-2, are summarized in Figure 2.

Fig2. Biological actions of the glucagon-like peptides. (A) The biological actions of glucagon-like peptide, GLP-1, are illustrated in the left panel. They include the following: intestine (secretion of GLP-1), pancreas (reduction in glucagon secretion and an increase in glucose-dependent secretion of insulin and somatostatin), stomach (reduction in gastric emptying), and brain (sensations of satiety and decreased appetite) are illustrated. (B) The biological actions of GLP-2 are tabulated in the right panel. The source of GLP-1 and GLP-2 is illustrated in Figure 1.

Oxyntomodulin binds to both the glucagon and GLP-1 receptor (GLP-1R); however, as yet a separate OXY receptor has not been identified. OXY is released postprandially and has the ability to pass through the blood-brain barrier and act as a satiety signal via effects on appetite centers such as the hypothalamus and brainstem.

The glucagon receptor is a member of the super family of G-protein-coupled receptors; it is a seven-transmembrane-spanning G protein coupled receptor. When it has bound glucagon it becomes activated and produces cAMP and intracellular Ca2+ as second messengers. Its molecular weight is ~62 kDa. The glucagon receptors are principally expressed in kidney and liver and are also found in lower amounts in adipose tissue, heart, adrenal glands, GI tract, and the cerebral cortex. Glucose is the dominant regulator of glucagon secretion. Falling levels of glucose stimulates glucagon secretion, while elevated levels of blood glucose decrease glucagon secretion.

The GLP-1 receptor also generates its biological responses through activation of a G protein-coupled receptor that is a member of the glucagon/secretin receptor superfamily. The GLP-1 activated second messengers are through calcium and cAMP stimulated pathways. Also a GLP-2 receptor has a separate G-protein activated receptor whose amino acid sequence is related to both the GLP-1 and glucagon receptors.

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