The role of glucagon on type 2 diabetes at a glance

Diabetology & Metabolic Syndrome

Amélio F Godoy-Matos¹ 

[1] Metabolism Unit, Instituto Estadual de Diabetes e Endocrinologia, Rio de Janeiro and Catholic University, Rio de Janeiro, Brazil

关键词: GLP-1;    Incretin effect;    Hiperglucagonemia;    Type 2 diabetes;   

Others  :  1115030
DOI  :  10.1186/1758-5996-6-91

 received in 2014-06-27, accepted in 2014-08-20,  发布年份 2014

【 摘 要 】

The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized. Inappropriately increased alpha-cell function importantly contributes to hyperglycemia and reflects the loss of tonic restraint normally exerted by high local concentrations of insulin on alpha-cells, possibly as a result of beta-cell failure and alpha-cell insulin resistance, but additional mechanisms, such as the participation of incretin hormones in this response, have also been suggested. Three classes of drugs already available for clinical use address the abnormalities of glucagon secretion in T2D, namely, the GLP-1 receptor agonists (GLP-1RA), the inhibitors of dipeptidyl peptidase-4 (DPP-4i) and the amylin agonist pramlintide; it has been proposed that the glucagonostatic and insulinotropic effects of GLP-1RA equally contribute to their hypoglycemic efficacy. In this review, the control of glucagon secretion and its participation in T2D pathogenesis are summarized.

【 授权许可】

   
2014 Godoy-Matos; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Murlin JR, Clough HD, Gibbs CBF, Stokes AM: Aqueous extracts of the pancreas. 1. Influence on the carbohydrate metabolism of depancreatized animals. J Biol Chem 1923, 56:253-296.
• [2]Sutherland EW, De Duve C: Origin and distribution of the hyperglycemic-glycogenolytic factor of the pancreas. J Biol Chem 1948, 175:663-674.
• [3]Unger RH, Eisentraut AM, Mc CM, Keller S, Lanz HC, Madison LL: Glucagon antibodies and their use for immunoassay for glucagon. Proc Soc Exp Biol Med 1959, 102:621-623.
• [4]Walker JN, Ramracheya R, Zhang Q, Johnson PR, Braun M, Rorsman P: Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? Diabetes Obes Metab 2011, 13(Suppl 1):95-105.
• [5]Gromada J, Franklin I, Wollheim CB: Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 2007, 28:84-116.
• [6]Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB: Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 2005, 54:1808-1815.
• [7]Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q: Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab 2006, 3:47-58.
• [8]Bansal P, Wang Q: Insulin as a physiological modulator of glucagon secretion. Am J Physiol Endocrinol Metab 2008, 295:E751-E761.
• [9]Osundiji MA, Evans ML: Brain control of insulin and glucagon secretion. Endocrinol Metab Clin North Am 2013, 42:1-14.
• [10]Tuduri E, Marroqui L, Soriano S, Ropero AB, Batista TM, Piquer S, Lopez-Boado MA, Carneiro EM, Gomis R, Nadal A, Quesada I: Inhibitory effects of leptin on pancreatic alpha-cell function. Diabetes 2009, 58:1616-1624.
• [11]Gedulin BR, Rink TJ, Young AA: Dose–response for glucagonostatic effect of amylin in rats. Metabolism 1997, 46:67-70.
• [12]Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132:2131-2157.
• [13]Heller RS, Aponte GW: Intra-islet regulation of hormone secretion by glucagon-like peptide-1-(7–36) amide. Am J Physiol 1995, 269:G852-G860.
• [14]Marchetti P, Lupi R, Bugliani M, Kirkpatrick CL, Sebastiani G, Grieco FA, Del Guerra S, D’Aleo V, Piro S, Marselli L, Boggi U, Filipponi F, Tinti L, Salvini L, Wollheim CB, Purrello F, Dotta F: A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 2012, 55:3262-3272.
• [15]Tornehave D, Kristensen P, Romer J, Knudsen LB, Heller RS: Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem 2008, 56:841-851.
• [16]Moens K, Heimberg H, Flamez D, Huypens P, Quartier E, Ling Z, Pipeleers D, Gremlich S, Thorens B, Schuit F: Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 1996, 45:257-261.
• [17]Heller RS, Kieffer TJ, Habener JF: Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes 1997, 46:785-791.
• [18]De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, Habib AM, Moritoh Y, Zang E, Reimann F, Rosengren AH, Shibasaki T, Gribble F, Renström E, Seino S, Eliasson L, Rorsman P: GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab 2010, 11:543-553.
• [19]de Heer J, Rasmussen C, Coy DH, Holst JJ: Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia 2008, 51:2263-2270.
• [20]Muoio DM, Newgard CB: Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008, 9:193-205.
• [21]Lim M, Park L, Shin G, Hong H, Kang I, Park Y: Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann N Y Acad Sci 2008, 1150:311-315.
• [22]Nauck M, Stockmann F, Ebert R, Creutzfeldt W: Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986, 29:46-52.
• [23]Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W: Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986, 63:492-498.
• [24]Meier JJ, Nauck MA: Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes 2010, 59:1117-1125.
• [25]Vilsboll T, Knop FK, Krarup T, Johansen A, Madsbad S, Larsen S, Hansen T, Pedersen O, Holst JJ: The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab 2003, 88:4897-4903.
• [26]An Z, Prigeon RL, D’Alessio DA: Improved glycemic control enhances the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2013, 98:4702-4708.
• [27]Holst JJ, Knop FK, Vilsboll T, Krarup T, Madsbad S: Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 2011, 34(Suppl 2):S251-S257.
• [28]Hansen KB, Vilsboll T, Bagger JI, Holst JJ, Knop FK: Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 2010, 95:3309-3317.
• [29]Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM: Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 1970, 49:837-848.
• [30]Menge BA, Gruber L, Jorgensen SM, Deacon CF, Schmidt WE, Veldhuis JD, Holst JJ, Meier JJ: Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. Diabetes 2011, 60:2160-2168.
• [31]Borghi VC, Wajchenberg BL, Cesar FP: Plasma glucagon suppressibility after oral glucose in obese subjects with normal and impaired glucose tolerance. Metabolism 1984, 33:1068-1074.
• [32]Ferrannini E, Muscelli E, Natali A, Gabriel R, Mitrakou A, Flyvbjerg A, Golay A, Hojlund K: Relationship between insulin S, cardiovascular disease risk project I: association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia 2007, 50:2342-2347.
• [33]Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, Herrera PL, Polonsky KS, McGuinness OP, Kulkarni RN: Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab 2009, 9:350-361.
• [34]Unger RH, Orci L: Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A 2010, 107:16009-16012.
• [35]Lund A, Vilsboll T, Bagger JI, Holst JJ, Knop FK: The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am J Physiol Endocrinol Metab 2011, 300:E1038-E1046.
• [36]Dor Y, Glaser B: beta-cell dedifferentiation and type 2 diabetes. N Engl J Med 2013, 368:572-573.
• [37]Unger RH, Cherrington AD: Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 2012, 122:4-12.
• [38]Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH: Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 2011, 60:391-397.
• [39]Omar BA, Andersen B, Hald J, Raun K, Nishimura E, Ahren B: Fibroblast growth factor 21 (FGF21) and glucagon like-peptide 1 contribute to diabetes resistance in glucagon receptor deficient mice. Diabetes 2014, 63:101-110.
• [40]D’Alessio DA: Taking aim at islet hormones with GLP-1: is insulin or glucagon the better target? Diabetes 2010, 59:1572-1574.
• [41]Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, Holst JJ: The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 2010, 59:1765-1770.
• [42]Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A: Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004, 89:2078-2084.
• [43]Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O: One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004, 53:1187-1194.
• [44]Kielgast U, Krarup T, Holst JJ, Madsbad S: Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care 2011, 34:1463-1468.