Glucagon is a 29 amino acid peptide hormone liberated in the α cells of the islets of Langerhans. For an overview of glucagon action, see the section on the Glucagon receptor
Glucagon-producing α cells represent one of the earliest populations of detectable islet cells in the developing endocrine pancreas.Glucagonis generally viewed as a hormone that opposes the action of insulin in peripheral tissues, predominantly the liver, where the insulin:glucagonratio determines the intricate control of gluconeogenesis and glycogenolysis. The action of glucagonin the liver is complex and involves coordinate regulation of transcription factors and signal transduction networks which converge on regulation of amino acid, lipid and carbohydrate metabolism. For an overview of selected recent insights into the downstream signals activated following engagement of the hepatic glucagon receptor, see CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001 Sep 13;413(6852):179-83 and CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-mgama. Nature. 2003 Nov 13;426(6963):190-3. and Glucagon represses signaling though the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004 Oct 19 [Epub ahead of print].
Although meals generally suppress glucagonsecretion from the normal α cell, subjects with diabetes frequently exhibit disordered control of glucagonsecretion leading to excess hepatic glucose production.
Glucagon biosynthesis
The tissue-specific liberation of proglucagon is controlled by cell-specific expression of prohormone convertase (PC) enzymes. An essential role for PC2 in the processing of islet proglucagon is revealed by studies of the PC2 knockout mouse. This mouse has mild hypoglycemia, elevated proinsulin, and exhibits a major defect in the processing of proglucagon to mature pancreatic glucagon, and the murine islet α cells secrete proglucagon from atypical secretory granules. See Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J Biol Chem. 1998 Feb 6;273(6):3431-7 and Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J Biol Chem. 2001 Jul 20;276(29):27197-202
A major component of the phenotype exhibited by the PC2 knockout mouse, namely mild hypoglycemia and marked alpha cell hyperplasia, appears attributable to defective levels of circulating glucagon, as glucagon replacement by osmotic mini-pump corrected hypoglycemia and produced a significant decrease in the number of hyperplastic alpha cells. The islet remodeling was detectable by 11 days, and after 25 days, PC2-/- islets resembled wild type islets. Apoptosis of islet α cells appears to contribute to the remodeling process, implying an important role for a threshold of circulating glucagonin the regulation of both islet α cell proliferation and survival. See Glucagon Replacement via Micro-Osmotic Pump Corrects Hypoglycemia and ?-Cell Hyperplasia in Prohormone Convertase 2 Knockout Mice. Diabetes. 2002 Feb;51(2):398-405
Glucagonis also synthesized in the CNS, where its actions may include regulation of peripheral glucoregulation, yet remain less well understood.
Glucagon release is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin. The inhibitory effect of somatostatin appears to be mediated via the SST-2 receptor, as revealed through studies using a SST-2-selective receptor antagonist DC-41-33. This compound enhanced glucagonrelease in studies using isolated rat islets, perifused isolated rat islets, and isolated perfused rat pancreas, as shown in Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats. Diabetes. 2003 May;52(5):1176-81
Glucagon Secretion
How does the islet a-cell sense and respond to changes in blood glucose and what goes wrong in the face of repeated hypoglycemia?
At present, there is very little known about the factors which directly regulate α-cell secretion. Insulin is a potent inhibitor of islet glucagonrelease. Somatostatin and GLP-1 also inhibit glucagonsecretion. Glucose suppresses glucagonsecretion, but may do so indirectly through insulin or GABA as outlined in Glucagon response to hypoglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats. Endocrinology. 1996 Aug;137 (8):3193-9 and Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes. Endocrinology. 1998 Nov;139(11) :4540-6 and Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature. 1989 Sep 21;341(6239):233-6.
Classical studies of isolated α-cells by Pipeleers and colleagues have demonstrated important differences between α vs. β-cells and their respective responses to varying glucose concentrations. Early classical studies demonstrated how glucose, nutrients, insulin and somatostatin regulate glucagon secretion and signal transduction pathways in purified rat α-cells as outlined in Interplay of nutrients and hormones in the regulation of glucagon release. Endocrinology. 1985 Sep;117(3):817-23.
In purified rat β-cells, the intracellular concentration of glucose or 3-O-methyl-D-glucose equilibrates within 2 min with the extracellular levels, and, like in intact islets, the rate of glucose oxidation displays a sigmoidal dose-response curve for glucose. In contrast, even after 5 min of incubation, the apparent distribution space of D-glucose or 3-O-methyl-D-glucose in a-cells remains much lower than the intracellular volume. In a-cells, both the rate of 3-O-methyl-D-glucose uptake and glucose oxidation proceed proportional to the hexose concentration up to 10 mM and reach saturation at higher concentrations, whereas exogenous insulin failed to affect 3-O-methyl-D-glucose or D-glucose uptake and glucose oxidation by purified α-cells See Differences in glucose handling by pancreatic A- and B-cells. J Biol Chem. 1984 Jan 25;259(2):1196-200.
Studies using rat islets, isolated purified α-cells, and GABA antagonists have provided evidence that GABA receptor subunits are expressed in α cells and that inhibition of GABA receptor activation is associated with complete failure of glucose to suppress glucagon secretion. See Glucose Inhibition of Glucagon Secretion From Rat alpha-Cells Is Mediated by GABA Released From Neighboring beta-Cells. Diabetes. 2004 Apr;53(4):1038-45
Elegant studies from Wang and colleagues demonstrate that insulin induces activation of GABA(A) receptors in the alpha cells by GABA receptor translocation via an Akt kinase-dependent pathway. This leads to membrane hyperpolarization in the alpha cells and, ultimately, suppression of glucagon secretion. Hence, insulin may directly inhibit glucagon secretion, and indirectly potentiate the inhibitory effects of GABA concomitant released by β-cells-See Intra-islet insulin suppresses glucagon release via GABA-GABA(A) receptor system. Cell Metab. 2006 Jan;3(1):47-58
Furthermore, the α cell secretory response may be modified, in an autoregulatory pathway, by secretion of L-glutamate which in turn triggers the secretion of gamma-aminobutyric acid (GABA) from β-cells. See Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by alpha-Cells of Islet of Langerhans. Diabetes. 2004 Apr;53(4):998-1006.
Insulin and zinc are potent inhibitors of glucagon secretion from rat α cells, perhaps through modulation of KATP channel activity, whereas the inhibitory effect of GLP-1 on α-cells may be indirect, as outlined in studies of rat α cells in vitro β-Cell Secretory Products Activate a-Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release. Diabetes. 2005 Jun;54(6):1808-15, and in experiments with mouse α- β-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1. Diabetes 2005 54: 482-491.
In contrast, similar experiments using isolated murine α cells demonstrate that glucose and insulin but not zinc exerts an inhibitory effect on regulation of glucagonsecretion in normal murine islets, dissociated a-cells, or the aTC-1 cell line, as demonstrated in Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic a-Cells. Diabetes. 2005 Jun;54(6):1789-9
A contrasting study using the perfused diabetic Wistar rat pancreas came to opposite conclusions, namely a decrement in the local concentration of zinc, but not insulin, resulted in improvement in the α-cell function. See Zinc, Not Insulin, Regulates the Rat Alpha Cell Response to Hypoglycemia in vivo. Diabetes. 2007 Feb 22; [Epub ahead of print]
The direct effect of glucose on pancreatic α-cells is difficult to study due to the challenge of isolating a pure α-cell population independent of contaminating β-cells. Glucose generally inhibits α-cells in the context of whole islets. A biphasic response of glucose-regulated α-cells, with inhibition of Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells. Endocrinology. 2005 Nov;146(11):4861-70. and in Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes. 2006 Aug;55(8):2318-23. Similarly, whereas raising the glucose concentration to 20 mM significantly increased the amount of Ca2+ entering beta cells, the sugar was without effect on Ca2+ entry into the alpha-cells as described in Glucose stimulates the entry of Ca2+ into the insulin-producing beta cells but not into the glucagon-producing alpha 2 cells. Acta Physiol Scand. 1987 Oct;131(2):230-4. The importance of somatostatin for glucose-mediated suppression of glucagon secretion is illustrated by studies using SST-/- mice, which fail to exhibit glucose-mediated suppression of glucagon secretion in studies using isolated islets Somatostatin secreted by islet cells fulfils multiple roles as a paracrine regulator of islet function. Diabetes November 4, 2008 10.2337/db08-0792
Intriguingly, gastrin has been shown to stimulate glucagon secretion in some but not all experimental models, and the fetal endocrine pancreas contains a large amount of gastrin, following which islet gastrin expression diminishes postnatally. Gastrin, together with EGF receptor ligands, may promote expansion of islet mass through enhanced islet neogenesis. Mice with disruption of the gastrin gene exhibit normal islets and basal levels of pancreatic glucagoncontent, yet exhibit mild hypoglycemia a defective glucagon secretory response to insulin induced hypoglycemia. See Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene Gastroenterology 2003 125:1164-174
An important role for the insulin receptor, and by inference insulin, in the control of a-cell function was demonstrated by Kawamori and colleagues in their analysis of a mouse with a-cell-specific deletion of the insulin receptor. These mice exhibited modest hyperglucagonemia in the basal fed state, and enhanced glucagon secretion in response to arginine or hypoglycemia. These findings imply that basal insulin receptor signaling is important for tonic inhibition of the a-cell. Insulin signaling in alpha cells modulates glucagon secretion in vivo Cell Metab. 2009 Apr;9(4):350-61.
Glucagon degradation and clearance
The mechanisms regulating degradation and clearance of glucagon remain incompletely understood. The enzyme neutralendopeptidase 24.11 has been shown to regulate the levels of glucagon in pigs. Studies using candoxatril, a selective NEP inhibitor, demonstrated that levels of both endogenous and exogenously infused glucagon are increased following candoxatril administration as shown in Neutral endopeptidase 24.11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E431-8. and Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept. 1995 Aug 22;58(3):149-56
Glucagon has also been shown to be a pharmacological substrate for DPP-4 in vitro Metabolism of glucagon by dipeptidyl peptidase IV (CD26). Regul Pept. 2001 Jan 12;96(3):133-41 and Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. J Biol Chem. 2000 Feb 11;275(6):3827-34. however whether DPP-4 regulates physiological levels of endogenous glucagon remains unclear.
As but one example, levels of intact glucagon are not significantly changed in pigs subjected to treatment with a DPP-4 inhibitor, with the kidney functioning as a major determinant for glucagon elimination Differential regional metabolism of glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E552-60.
Glucagon action
The key biological actions of glucagon converge on regulation of glucose homeostasis through enhanced synthesis and mobilization of glucose in the liver.Glucagon receptors are also expressed on human islet b cells and in some experiments, may contribute to the regulation of glucose-stimulated insulin secretion as shown in Diabetologia 2000 Aug;43(8):1012-9. The relative importance of glucagon and GLP-1 for augmentation of the insulin secretory response to high glucose (20 mM) was also examined in the perfused rat pancreas preparation, wherein neither the GLP-1 receptor antagonist exendin(9-39) or the glucagonreceptor antagonist [des-His1-des-Phe6,Glu9] glucagon-NH2 inhibited the insulin secretory response to hyperglycemia. Similarly, augmenting endogenous glucagon secretion using isoproterenol had no effect on glucose-induced insulin secretion. Hence the precise physiological actions of glucagon receptors on islet b -cells remains a subject for ongoing investigation. See Assessment of the Role of Interstitial Glucagon in the Acute Glucose Secretory Responsiveness of In Situ Pancreatic beta-Cells. Diabetes. 2002 Mar;51(3):669-75
Glucagon generally functions as a counter-regulatory hormone, opposing the actions of insulin, and maintaining the levels of blood glucose, particularly in patients with hypoglycemia. In patients with diabetes, excess glucagon secretion plays a primary role in the metabolic perturbations associated with diabetes, such as hyperglycemia. Although the molecular control of α cell function leading to excess glucagon secretion is not well understood, individuals with a single amino acid polymorphism, Glu23Lys in the KIR6.2 potassium channel exhibit higher levels of glucose during an OGTT and defective glucose-mediated suppression of glucagon secretion in vivo. See The Prevalent Glu23Lys Polymorphism in the Potassium Inward Rectifier 6.2 (KIR6.2) Gene Is Associated With Impaired Glucagon Suppression in Response to Hyperglycemia. Diabetes. 2002 Sep;51 (9): 2854-60.
A major problem in diabetic patients with repeated hypoglycemia is the development of defective counter-regulatory responses that include reduced or absent glucagon responses to hypoglycemia. Hence understanding how and why the autonomic nervous system and islet α cell develop defects in glucagonsecretion leading to hypoglycemia insensitivity is a major challenge in diabetes research.
Administration of glucagon pharmacologically leads to a rapid rise in blood glucose, hence injectable glucagon is used as a pharmacological treatment for diabetic patients at risk for significant hypoglycemia. See Glucagon, Hypoglycemia and Counterregulation
Given the central importance of glucagon for blood sugar control, glucagon antagonists are also being developed for possible therapeutic use in patients with diabetes. For an overview, see Glucagon Receptor Antagonists
To review the importance of glucagon receptor signaling, see Glucagon Receptor
Although glucagon-producing tumors in human subjects are rare, they may be associated with clinical manifestations such as mucositis, anemia, weight loss, and necrolytic migratory erythema, in addition to hyperglycemia and rarely, intestinal hyperplasia.
See Glucagon, Hypoglycemia and Counterregulation
A number of studies have demonstrated that glucagonpromotes degradation of fat (known as lipolysis) both in cell preparations and in vivo. Does glucagon promote lipolysis in human adipose tissue? Older studies had been contradictory, with some reports affirming a role for glucagon in human adipocyte lipolysis Human glucagon and vasoactive intestinal polypeptide (VIP) stimulate free fatty acid release from human adipose tissue in vitro, whereas other experiments failed to show significant effects of glucagon on lipolysis in isolated human fat cells Glycerol release from incubated human adipocytes is not affected by gastrointestinal peptides. Int J Obes. 1985;9(1):25-7.
Intriguingly, low dose glucagon together with GLP-1R activation produces near synergestic efficacy with regard to weight loss, lipolysis, and glucose homeostasis in rodent. Thee action recapitulate, to some extent, the profile of actions described for oxyntomodulin, a peptide that exerts dual Gcgr:GLP-1R agonism. See A new glucagon and GLP-1 co-agonist eliminates obesity in rodents Nature Chemical Biology Published online: 13 July 2009 | doi:10.1038/nchembio.209 and GLP-1/GCGR dual agonism reverses obesity in mice Diabetes ; published ahead of print July 14, 2009, doi:10.2337/db09-0278
Glucagonwithdrawal or physiological hyperglucagonemia in vivo did not produce significant changes in palmitate flux, an index of lipolysis, in normal or diabetic human subjects Effects of glucagon on free fatty acid metabolism in humans. J Clin Endocrinol Metab. 1991 Feb;72(2):308-15.
Similar negative findings were reported in the May 2001 issue of the JCEM, wherein 7 healthy male subjects were implanted with indwelling microdialysis catheters in the abdominal wall, and the effects of glucagoninfusion on interstitial glycerol, and plasma glycerol and FFAs were examined. No effects on glycerol or free fatty acids were detected with systemic glucagon infusion, with or without exogenous glucose. See Physiological Levels of Glucagon Do Not Influence Lipolysis in Abdominal Adipose Tissue as Assessed by Microdialysis. J Clin Endocrinol Metab. 2001 May 1;86(5):2085-2089. Similar negative results were obtained in a study of lipolysis in normal male subjects with indwelling microdialysis catheters implanted into abdominal adipose tissue Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. J Clin Endocrinol Metab. 2001 May;86(5):2085-9. Hence, the available data does not support an important physiological role for glucagon in lipolysis.
Glucagon has anti-motility effects on the gastrointestinal tract (esophagus, stomach, and small and large intestine) when administered pharmacologically to human subjects. See Glucagon effects on the human small intestine. Dig Dis Sci. 1979 Jul;24(7):501-8 and Glucagon and the colon. Gut. 1975 Dec;16(12):973-8 and A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med. 1999 Nov 11;341(20):1496-503. Glucagon may also relax smooth muscle in the gallbladder and ureter, leading to occasional use during radiology studies of the gallbladder and kidney.
Administration of glucagonto human subjects leads to a rapid increase in blood glucose after either iv or intramuscular (IM) injection. Curiously, IM, but not IV glucagon, seems to activate components of the HPA axis (ACTH and cortisol predominantly). The mechanisms underlying this difference are not clear. See Glucagon is an ACTH secretagogue as effective as hCRH after intramuscular administration while it is ineffective when given intravenously in normal subjects. Pituitary. 2000 Nov;3(3):169-73.
Glucagon and Taste
Periodic studies have examined the importance of glucagon for taste sensing. Elson and colleagues reported local co-expression of the proglucagon gene and the Gcgr in subsets of murine lingual taste buds the majority of which also expressed PLCb2 and T1R3, a subunit of the sweet/umami taste receptors. The Gcgr antagonist L-168,048 exhibited reduced taste responsiveness in the presence of sucrose, suggesting a role for glucagon in sweet taste responsivity Glucagon signaling modulates sweet taste responsiveness. FASEB J. 2010 Jun 14. [Epub ahead of print]
Miniglucagon
Several studies, principally from the laboratory of D Bataille, have documented that a proteolytic fragment of 29 amino acid glucagon, glucagon (19-29), is liberated following cleavage of glucagon at the Arg17-Arg18 amino acid doublet. Processing may occur locally in target tissues such as the pancreas, liver or heart, as well as in the circulation Endopeptidase from rat liver membranes, which generates miniglucagon from glucagon. J Biol Chem. 1993 Oct 15;268(29):21748-53. To date, a separate receptor for miniglucagon has not been identified, although various actions have been ascribed to this peptide, including effects in the liver, heart and pancreas, including inhibition of insulin secretion Miniglucagon (glucagon 19-29), a potent and efficient inhibitor of secretagogue-induced insulin release through a Ca2+ pathway. J Biol Chem. 1999 Apr 16;274(16):10869-76. See Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells. Circ Res. 1996 Jan;78(1):102-9; and Glucagon-(19-29) exerts a biphasic action on the liver plasma membrane Ca2+ pump which is mediated by G proteins. J Biol Chem. 1990 Jun 15;265(17):9876-80.