Current Diabetes Reports

, 14:555 | Cite as

Glucagon and Type 2 Diabetes: the Return of the Alpha Cell

  • Asger Lund
  • Jonatan I. Bagger
  • Mikkel Christensen
  • Filip K. Knop
  • Tina Vilsbøll
Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Abstract

In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes suffer from fasting and postprandial hyperglucagonemia, which stimulate hepatic glucose production and, thus, contribute to the hyperglycemia characterizing these patients. Although this has been known for years, research focusing on alpha cell (patho)physiology has historically been dwarfed by research on beta cells and insulin. Today the mechanisms behind type 2 diabetic hyperglucagonemia are still poorly understood. Preclinical and clinical studies have shown that the gastrointestinal hormone glucose-dependent insulinotropic polypeptide (GIP) might play an important role in this pathophysiological phenomenon. Furthermore, it has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with type 2 diabetes. In this review, we focus on the regulation of glucagon secretion by the incretin hormones glucagon-like peptide-1 (GLP-1) and GIP. Furthermore, potential advantages and limitations of suppressing glucagon secretion or antagonizing the glucagon receptor, respectively, in the treatment of patients with type 2 diabetes will be discussed.

Keywords

Alpha cell Glucagon GIP GLP-1 Type 2 diabetes 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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.PubMedCrossRefGoogle Scholar
  2. 2.
    Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (first two parts). N Engl J Med. 1981;304:1518–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975;1:14–6.PubMedCrossRefGoogle Scholar
  4. 4.••
    Lee Y, Wang M-Y, Du XQ, Charron MJ, Unger RH. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes. 2011;60:391–7. This study shows that in the presence of glucagon deficiency, complete lack of insulin does not result in hyperglycemia—highlighting the role of glucagon on hyperglycemia.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Hvidberg A, Nielsen MT, Hilsted J, Ørskov C, Holst JJ. Effect of glucagon-like peptide-1 (proglucagon 78-107 amide) on hepatic glucose production in healthy man. Metabolism. 1994;43:104–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Hare KJ, Knop FK, Asmar M, Madsbad S, Deacon CF, Holst JJ, et al. Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:4679–87.PubMedCrossRefGoogle Scholar
  7. 7.
    Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE, et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia. 2003;46:798–801.PubMedCrossRefGoogle Scholar
  8. 8.
    Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991;260:E67–74.PubMedGoogle Scholar
  9. 9.
    Rocha DM, Faloona GR, Unger RH. Glucagon-stimulating activity of 20 amino acids in dogs. J Clin Invest. 1972;51:2346–51.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Ahrén B. Autonomic regulation of islet hormone secretion—implications for health and disease. Diabetologia. 2000;43:393–410.PubMedCrossRefGoogle Scholar
  11. 11.
    Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006;3:47–58.PubMedCrossRefGoogle Scholar
  12. 12.
    Luft R, Efendić S, Hökfelt T. Somatostatin—both hormone and neurotransmitter? Diabetologia. 1978;14:1–13.PubMedCrossRefGoogle Scholar
  13. 13.
    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;51:2263–70.PubMedCrossRefGoogle Scholar
  14. 14.
    Gedulin BR, Rink TJ, Young AA. Dose-response for glucagonostatic effect of amylin in rats. Metabolism. 1997;46:67–70.PubMedCrossRefGoogle Scholar
  15. 15.•
    Bagger JI, Knop FK, Lund A, Holst JJ, Vilsbøll T. Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia. 2014. This study describes the hyperglucagonemic response to oral glucose loads in patients with type 2 diabetes and suggests that this response may represent a pathological version of a gut-derived phenomenon.Google Scholar
  16. 16.
    Knop FK, Aaboe K, Vilsbøll T, Vølund A, Holst JJ, Krarup T, et al. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab. 2012;14:500–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Dunning BE, Foley JE, Ahrén B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia. 2005;48:1700–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1987;64:106–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia. 1995;38:337–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4053–9.PubMedGoogle Scholar
  21. 21.
    Knop FK, Vilsbøll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia. 2007;50:797–805.PubMedCrossRefGoogle Scholar
  22. 22.
    Meier JJ, Deacon CF, Schmidt WE, Holst JJ, Nauck MA. Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects. Diabetologia. 2007;50:806–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Meier JJ. The contribution of incretin hormones to the pathogenesis of type 2 diabetes. Best Pract Res Clin Endocrinol Metab. 2009;23:433–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Santeusanio F, Faloona GR, Unger RH. Suppressive effect of secretin upon pancreatic alpha cell function. J Clin Invest. 1972;51:1743–9.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rushakoff RJ, Goldfine ID, Carter JD, Liddle RA. Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans. J Clin Endocrinol Metab. 1987;65:395–401.PubMedCrossRefGoogle Scholar
  26. 26.
    De Heer J, Pedersen J, Ørskov C, Holst JJ. The alpha cell expresses glucagon-like peptide-2 receptors and glucagon-like peptide-2 stimulates glucagon secretion from the rat pancreas. Diabetologia. 2007;50:2135–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Nauck MA, Weber I, Bach I, Richter S, Ørskov C, Holst JJ, et al. Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in type 2 diabetic patients. Diabet Med J Br Diabet Assoc. 1998;15:937–45.CrossRefGoogle Scholar
  28. 28.
    Chia CW, Carlson OD, Kim W, Shin Y-K, Charles CP, Kim HS, et al. Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes. 2009;58:1342–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Lund A, Vilsbøll 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:E1038–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Pederson RA, Brown JC. Interaction of gastric inhibitory polypeptide, glucose, and arginine on insulin and glucagon secretion from the perfused rat pancreas. Endocrinology. 1978;103:610–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Adrian TE, Bloom SR, Hermansen K, Iversen J. Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas. Diabetologia. 1978;14:413–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Elahi D, Andersen DK, Brown JC, Debas HT, Hershcopf RJ, Raizes GS, et al. Pancreatic alpha- and beta-cell responses to GIP infusion in normal man. Am J Physiol. 1979;237:E185–91.PubMedGoogle Scholar
  33. 33.
    Jensen SL, Holst JJ, Nielsen OV, Lauritsen KB. Secretory effects of gastric inhibitory polypeptide on the isolated perfused porcine pancreas. Acta Physiol Scand. 1981;111:233–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2:1300–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Brunicardi FC, Druck P, Seymour NE, Sun YS, Elahi D, Andersen DK. Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas. J Surg Res. 1990;48:273–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Dupre J, Caussignac Y, McDonald TJ, Van Vliet S. Stimulation of glucagon secretion by gastric inhibitory polypeptide in patients with hepatic cirrhosis and hyperglucagonemia. J Clin Endocrinol Metab. 1991;72:125–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Ding WG, Renström E, Rorsman P, Buschard K, Gromada J. Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes. 1997;46:792–800.PubMedCrossRefGoogle Scholar
  38. 38.•
    Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60:3103–9. This study describes the role of GIP on insulin and glucagon secretion during different glycemic levels and suggests that GIP is a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114:115–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–7.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Meier JJ, Hücking K, Holst JJ, Deacon CF, Schmiegel WH, Nauck MA. Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes. 2001;50:2497–504.PubMedCrossRefGoogle Scholar
  42. 42.
    Meier JJ, Gallwitz B, Kask B, Deacon CF, Holst JJ, Schmidt WE, et al. Stimulation of insulin secretion by intravenous bolus injection and continuous infusion of gastric inhibitory polypeptide in patients with type 2 diabetes and healthy control subjects. Diabetes. 2004;53 Suppl 3:S220–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Nauck M, Schmidt WE, Ebert R, Strietzel J, Cantor P, Hoffmann G, et al. Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab. 1989;69:654–62.PubMedCrossRefGoogle Scholar
  44. 44.
    Nauck MA, Bartels E, Ørskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab. 1993;76:912–7.PubMedGoogle Scholar
  45. 45.
    Pfeifer MA, Halter JB, Porte Jr D. Insulin secretion in diabetes mellitus. Am J Med. 1981;70:579–88.PubMedCrossRefGoogle Scholar
  46. 46.
    Vilsbøll T, Knop FK, Krarup T, Johansen A, Madsbad S, Larsen S, et al. 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;88:4897–903.PubMedCrossRefGoogle Scholar
  47. 47.
    Hansen KB, Vilsbøll T, Bagger JI, Holst JJ, Knop FK. Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects. J Clin Endocrinol Metab. 2012;97:1363–70.PubMedCrossRefGoogle Scholar
  48. 48.
    Christensen M, Calanna S, Holst JJ, Vilsbøll T, Knop FK. Glucose-dependent insulinotropic polypeptide: blood glucose stabilizing effects in patients with type 2 diabetes. J Clin Endocrinol Metab. 2013;jc20133644.Google Scholar
  49. 49.
    Ørskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988;123:2009–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Edwards CM, Todd JF, Mahmoudi M, Wang Z, Wang RM, Ghatei MA, et al. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999;48:86–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 1985;28:574–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Hope KM, Tran POT, Zhou H, Oseid E, Leroy E, Robertson RP. Regulation of alpha-cell function by the beta-cell in isolated human and rat islets deprived of glucose: the “switch-off” hypothesis. Diabetes. 2004;53:1488–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Raju B, Cryer PE. Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. Diabetes. 2005;54:757–64.PubMedCrossRefGoogle Scholar
  54. 54.
    Hare KJ, Vilsbøll T, Holst JJ, Knop FK. Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab. 2010;298:E832–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Kielgast U, Holst JJ, Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual beta-cell function. Diabetes. 2011;60:1599–607.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors. Diabetologia. 2005;48:612–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Balkan B, Li X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1449–54.PubMedGoogle Scholar
  58. 58.
    Holst JJ, Schwartz TW, Knuhtsen S, Jensen SL, Nielsen OV. Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas. J Auton Nerv Syst. 1986;17:71–84.PubMedCrossRefGoogle Scholar
  59. 59.
    Plamboeck A, Veedfald S, Deacon CF, Hartmann B, Wettergren A, Svendsen LB, et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol. 2013;304:G1117–27.PubMedCrossRefGoogle Scholar
  60. 60.
    Hare KJ, Vilsbøll 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;59:1765–70.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239–46.PubMedCrossRefGoogle Scholar
  62. 62.
    Shah P, Basu A, Basu R, Rizza R. Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol. 1999;277:E283–90.PubMedGoogle Scholar
  63. 63.
    Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39:1381–90.PubMedCrossRefGoogle Scholar
  64. 64.
    Holst JJ, Christensen M, Lund A, de Heer J, Svendsen B, Kielgast U, et al. Regulation of glucagon secretion by incretins. Diabetes Obes Metab. 2011;13 Suppl 1:89–94.PubMedCrossRefGoogle Scholar
  65. 65.
    Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–42.PubMedCrossRefGoogle Scholar
  66. 66.
    Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, et al. 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;53:1187–94.PubMedCrossRefGoogle Scholar
  67. 67.
    Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–36.PubMedCrossRefGoogle Scholar
  68. 68.
    Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Bagger JI, Knop FK, Holst JJ, Vilsbøll T. Glucagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes Metab. 2011;13:965–71.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Asger Lund
    • 1
    • 2
  • Jonatan I. Bagger
    • 1
    • 2
  • Mikkel Christensen
    • 1
    • 2
    • 3
  • Filip K. Knop
    • 1
    • 2
  • Tina Vilsbøll
    • 1
  1. 1.Center for Diabetes Research, Department of Medicine, Gentofte HospitalUniversity of CopenhagenHellerupDenmark
  2. 2.Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Clinical Pharmacology, Bispebjerg HospitalUniversity of CopenhagenCopenhagenDenmark

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