Other entities represented in this entry:
HGNC Approved Gene Symbol: GCG
Cytogenetic location: 2q24.2 Genomic coordinates (GRCh38) : 2:162,142,882-162,152,247 (from NCBI)
Glucagon is a 29-amino acid pancreatic hormone that counteracts the glucose-lowering action of insulin by stimulating glycogenolysis and gluconeogenesis. Human, rabbit, rat, pig, and cow glucagons are identical. Glucagon is a member of a multigene family that includes secretin (182099), vasoactive intestinal peptide (VIP; 192320), gastric inhibitory peptide (GIP; 137240), glicentin, and others.
Bell et al. (1983) analyzed the structure of the preproglucagon gene. It contains at least 3 intervening sequences that divide the protein-coding portion into 4 regions corresponding to the signal peptide and part of the N-terminal peptide, the remainder of the N-terminal peptide and glucagon, glucagon-like peptide-1 (GLP1), and GLP2. Glucagon is encoded by exon 2. The organization of the human preproglucagon gene suggested to Bell et al. (1983) that tandem duplication, in either 1 or 2 steps, of an exon encoding glucagon or a GLP has occurred. This was considered to support Gilbert's notion (Gilbert, 1978) that the mosaic structure of eukaryotic genes reflects their evolutionary history, with production of new proteins by reassortment and amplification of exons of existing proteins.
GLP1, also known as 7-37 for the codons of the preproglucagon molecule which encode it, renders pancreatic beta-cells 'glucose-competent' and may be useful in the treatment of noninsulin-dependent diabetes mellitus (Holz et al., 1993).
GLP1 is a potent insulin secretagogue. Wang et al. (1995) presented evidence that it plays a major role in the enteroinsular axis, accounting, for example, for the finding that plasma insulin levels accompanying oral intake of glucose are greater than those observed when glucose is given intravenously. It is the so-called gluco-incretin. Wang et al. (1995) used an inhibitor of GLP1, called exendin(9-39), which is a fragment of a peptide found in venom of gila monsters that binds tightly to the GLP1 receptor (GLP1R; 138032) without agonistic activity. Although GLP1 and its specific receptors are present in the hypothalamus, no physiologic role for central GLP1 had been established. Turton et al. (1996) found that intracerebroventricular GLP1 powerfully inhibited feeding in fasted rats. Injection of the specific antagonist, exendin, blocked the inhibitory effect of GLP1 on food intake. Exendin alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulus, neuropeptide Y (162640). Induction of FOS (164810) is a marker of neuronal activation. Following intracerebroventricular GLP1 injection, FOS appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin. Both of these regions of the brain are of primary importance in the regulation of feeding. The findings suggested that central GLP1 is a physiologic mediator of satiety.
Drucker (1999) reviewed the physiologic relevance of GLP2. GLP2 is secreted in a nutrient-dependent manner from enteroendocrine cells throughout the gastrointestinal tract and is trophic to the intestinal epithelial mucosa. It acts via stimulation of crypt cell proliferation and inhibition of cell death. GLP2 also stimulates intestinal glucose transport, decreases mucosal permeability, and has shown therapeutic efficacy in experimental models of short bowel syndrome and both small and large bowel inflammation.
Drucker (2001) noted that both GLP1 and GLP2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms. GLP2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP2 are evident in rodent models of experimental intestinal injury. GLP2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP2 are transduced by the GLP2 receptor (603659), a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The authors concluded that the cytoprotective, reparative, and energy-retentive properties of GLP2 suggest that GLP2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium.
GLP2 is metabolized extensively by dipeptidyl peptidase IV (DPP4; 102720) in rats. To elucidate its fate in humans, Hartmann et al. (2000) investigated GLP2 metabolism in healthy volunteers after (1) a 500-calorie mixed meal; (2) intravenous infusion of synthetic human GLP2; (3) a subcutaneous bolus injection; and (4) in vitro incubation in plasma and blood. GLP2 concentrations were determined by N-terminal RIA measuring only intact GLP2, side-viewing RIA measuring intact and degraded forms (e.g., GLP2-(3-33) arising from DPP4 degradation), and high performance liquid chromatography (HPLC). Meal ingestion elevated plasma GLP2 (intact, 16 +/- 3 to 73 +/- 10 pmol/L at 90 minutes), and HPLC revealed 2 immunoreactive components, intact GLP2 and GLP2-(3-33). The elimination t-1/2 values were 7.2 +/- 2 min (intact GLP2) and 27.4 +/- 5.4 min (GLP2-(3-33)), and MCRs were 6.8 +/- 0.6 and 1.9 +/- 0.3 mL/kg.min, respectively. Subcutaneous injection increased intact GLP2 to maximally 1,493 +/- 250 pmol/L at 45 minutes, whereas total GLP2 increased to 2,793 +/- 477 pmol/L at 90 minutes. Hartmann et al. (2000) concluded that GLP2 is extensively degraded to GLP2-(3-33) in humans, presumably by DPP4. Nevertheless, 69% remained intact 1 hour after GLP2 injection, supporting the possibility of subcutaneous use in patients with intestinal insufficiency.
Pancreatic beta cells share several molecular mechanisms with pancreatic endocrine cells in terms of development, therefore they may possess a potential for insulin expression. To test this idea, Suzuki et al. (2003) sought to induce insulin-production in intestinal epithelial progenitors by using glucagon-like peptide-1. They found that GLP1-(1-37) induces insulin production in developing and, to a lesser extent, adult intestinal epithelial cells in vitro and in vivo, a process mediated by upregulation of the Notch-related gene encoding neurogenin-3 (NGN3; 604882) and its downstream targets, which are involved in pancreatic endocrine differentiation. These cells became responsive to glucose challenge in vitro and reverse insulin-dependent diabetes after implantation into diabetic mice. The findings suggested that efficient induction of insulin production in intestinal epithelial cells by GLP1-(1-37) could represent a new therapeutic approach for diabetes mellitus. The experiments were performed in the cell and organ culture.
Hirasawa et al. (2005) found colocalization of GPR120 (609044) and GLP1 in human colonic intraepithelial neuroendocrine cells. Using several techniques, including RNA interference, they showed that mouse Gpr120 mediated free fatty acid-induced secretion of Glp1 in a mouse intestinal endocrine cell line.
Dyachok et al. (2006) introduced a new ratiometric evanescent-wave-microscopy approach to measure cAMP concentration beneath the plasma membrane and showed that insulin-secreting beta cells respond to glucagon and GLP1 with marked cAMP oscillations. Simultaneous measurements of intracellular calcium concentration revealed that the 2 messengers are interlinked and reinforce each other. Moreover, cAMP oscillations are capable of inducing rapid on-off calcium responses, but only sustained elevation of cAMP concentration induces nuclear translocation of the catalytic subunit of the cAMP-dependent protein kinase. Dyachok et al. (2006) concluded that their results established a new signaling mode for cAMP and indicated that temporal encoding of cAMP signals might constitute a basis for differential regulation of downstream cellular targets.
Jang et al. (2007) examined human duodenal biopsy specimens and found expression of the sweet taste receptors T1R2 (606226) and T1R3 (605865), alpha-gustducin (GNAT3; 139395), and other taste transduction elements in the enteroendocrine L cells. Mouse intestinal cells also expressed alpha-gustducin, and ingestion of glucose by Gnat3-null mice revealed deficiencies in secretion of GLP1 and the regulation of plasma insulin (176730) and glucose. Isolated small bowel and intestinal villi from Gnat3-null mice showed markedly defective GLP1 secretion in response to glucose. In human NCI-H716 L cells, GLP1 release was promoted by sugars and the artificial sweetener sucralose and blocked by the sweet-receptor antagonist lactisole or siRNA for alpha-gustducin. Jang et al. (2007) concluded that L cells of the gut 'taste' glucose through the same mechanism used by taste cells of the tongue.
Margolskee et al. (2007) demonstrated that dietary sugar and artificial sweeteners increased sodium-dependent glucose transporter SGLT1 (SLC5A1; 182380) mRNA and protein expression and increased glucose absorptive capacity in wildtype mice but not in knockout mice lacking T1R3 or alpha-gustducin. In mouse GLUTag enteroendocrine cells, sucralose increased the release of GLP1 and GIP (137240), gut hormones implicated in SGLT1 upregulation, and increased intracellular calcium; inhibition of the T1R2-T1R3 sweet taste receptor by gurmarin blocked the sucralose-stimulated release of GLP1 and GIP and the sucralose-dependent mobilization of calcium in GLUTag cells.
Maji et al. (2009) found that peptide and protein hormones, including GLP2, in secretory granules of the endocrine system are stored in an amyloid-like cross-beta-sheet-rich conformation, and concluded that functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.
Yore et al. (2014) identified a class of GLUT4 (SLC2A4; 138190)-regulated lipids, called fatty acid esters of hydroxy fatty acids (FAHFAs), in mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowered ambient glycemia and improved glucose tolerance while stimulating GLP1 and insulin secretion. PAHSAs also reduced adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 (609044) to enhance insulin-stimulated glucose uptake. Yore et al. (2014) thus concluded that FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.
He et al. (2019) described a subset of immune cells, integrin beta-7 (ITGB7; 147559)+ natural gut intraepithelial T lymphocytes (natural IELs), that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. ITGB7-null mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolemia, hypertension, diabetes, and atherosclerosis. Furthermore, He et al. (2019) showed that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP1, which is normally controlled by IELs through expression of the GLP1 receptor (GLP1R; 138032). In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP1. He et al. (2019) concluded that although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
Perry et al. (2020) showed that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase (608786) flux, while also increasing mitochondrial fat oxidation, all of which are mediated by stimulation of the inositol triphosphate receptor-1 (INSP3R1, also known as ITPR1; 147265). In rats and mice, chronic physiologic increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment, reversing hepatic steatosis and glucose intolerance, were abrogated in Insp3r1-knockout mice. Perry et al. (2020) suggested that their results provided insights into glucagon biology and suggested that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type 2 diabetes.
White and Saunders (1986) showed that the human glucagon gene is approximately 9.4 kb long and contains 6 exons and 5 introns.
Cryoelectron Microscopy
Liang et al. (2018) described the structure of the human GLP1 receptor (138032) in complex with a G protein-biased peptide exendin-P5 and a G-alpha(s) heterotrimer, determined at a global resolution of 3.3 angstroms by cryoelectron microscopy. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differed between the exendin-P5-bound structure and previously described GLP1-bound GLP1 receptor structure. At the intracellular face, there was a 6-degree difference in the angle of the G-alpha-s-alpha-5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the G-alpha(s) protein.
Tricoli et al. (1984) assigned glucagon to chromosome 2 by use of a DNA probe in somatic cell hybrids. By use of a DNA probe for in situ hybridization, Schroeder et al. (1984) assigned the gene to 2q36-2q37. In the mouse, glucagon is coded by chromosome 2 (Lalley et al., 1987).
Stumpf (2020) mapped the GCG gene to chromosome 2q24.2 based on an alignment of the GCG sequence (GenBank BC005278) with the genomic sequence (GRCh38).
In mice undergoing a hyperglycemic hyperinsulinemic clamp, Knauf et al. (2005) showed that intracerebrovascular administration of the GLP1R antagonist exendin(9-39) increased muscle glucose utilization and glycogen content, even in muscle insulin receptor (147670)-null mice. Conversely, intracerebrovascular infusion of the GLP1R agonist exendin-4 reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by intravenous infusion of glucose, intracerebrovascular exendin-4 caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. Knauf et al. (2005) concluded that during hyperglycemia, brain GLP1 inhibits muscle glucose utilization and increases insulin secretion to favor hepatic glycogen stores.
By adenovirus-mediated transduction of the prohormone convertase PC1 (PCSK1; 162150) into pancreatic alpha cells, Wideman et al. (2006) increased islet GLP1 secretion in vitro and observed improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. Transduced islets transplanted into a mouse model of type I diabetes showed superior ability to restore good glucose control compared to normal islets, with fasting blood glucose and glucose tolerance matching that of normal mice.
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