Diabetes Metab J.  2015 Feb;39(1):1-9. 10.4093/dmj.2015.39.1.1.

Pancreatic alpha-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block

• Moon JS
• Won KC

• KMID: 2280650
• DOI: http://doi.org/10.4093/dmj.2015.39.1.1

Abstract

Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from alpha-cell has languished whereas beta-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant alpha-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted alpha-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of alpha-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from alpha-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on alpha-cell dysfunction and therapeutic potentials of targeting alpha-cell in T2D.

Keyword

Diabetes mellitus, type 2; Glucagon; Glucagon-secreting cells; Insulin; Insulin-secreting cells

MeSH Terms

Diabetes Mellitus, Type 2
Fasting
Glucagon
Glucagon-Like Peptide 1
Glucagon-Secreting Cells
Glucose
Hyperglycemia
Hypoglycemia
Insulin
Insulin-Secreting Cells
Receptors, Glucagon
Glucagon
Glucagon-Like Peptide 1
Glucose
Insulin
Receptors, Glucagon

Figure

• 

  Fig. 1 Intra-islet insulin & glucagon secretion. Normal (in nondiabetes) and advanced type 2 diabetes (T2D) of the relationship between the inhibitory effects of pancreatic β-cell insulin secretion on pancreatic α-cell glucagon secretion. Normally, an increase in plasma glucose level causes an increase in β-cell insulin secretion that prevents an increase in α-cell glucagon secretion in response to meal. In advanced T2D, however, β-cell failure which is lack of intra-islet signaling result in not only fail to suppress but also an increase in pancreatic α-cell glucagon secretion (A). A decrease in plasma glucose level causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. On the other hand, in the advanced T2D, a decrease in plasma glucose cannot cause a decrease in β-cell insulin secretion, and the absence of that signal results in no increase in pancreatic α-cell glucagon secretion during hypoglycemia (B).

Reference

1. Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975; 1:14–16.

2. Moon JS, Ha KS, Yoon JS, Lee HW, Lee HC, Won KC. BETA study group. The effect of glargine versus glimepiride on pancreatic beta-cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open-label, randomized, controlled study. Acta Diabetol. 2014; 51:277–285.

3. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009; 58:773–795.

4. Hare KJ, Knop FK, Asmar M, Madsbad S, Deacon CF, Holst JJ, Vilsboll T. Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009; 94:4679–4687.

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. Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev. 2007; 28:253–283.

7. Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991; 260(1 Pt 1):E67–E74.

8. Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE, Nauck MA. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia. 2003; 46:798–801.

9. Rocha DM, Faloona GR, Unger RH. Glucagon-stimulating activity of 20 amino acids in dogs. J Clin Invest. 1972; 51:2346–2351.

10. Ahren B. Autonomic regulation of islet hormone secretion: implications for health and disease. Diabetologia. 2000; 43:393–410.

11. 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.

12. Gedulin BR, Rink TJ, Young AA. Dose-response for glucagonostatic effect of amylin in rats. Metabolism. 1997; 46:67–70.

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; 51:2263–2270.

14. Luft R, Efendic S, Hokfelt T. Somatostatin: both hormone and neurotransmitter? Diabetologia. 1978; 14:1–13.

15. Unger RH. Glucagon and insulin: a bihormonal system. Compr Ther. 1976; 2:20–26.

16. Muller WA, Faloona GR, Unger RH. Hyperglucagonemia in diabetic ketoacidosis. Its prevalence and significance. Am J Med. 1973; 54:52–57.

17. Orci L, Baetens D, Rufener C, Amherdt M, Ravazzola M, Studer P, Malaisse-Lagae F, Unger RH. Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes. Proc Natl Acad Sci U S A. 1976; 73:1338–1342.

18. Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia. 1995; 38:337–343.

19. Larsson H, Ahren B. Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care. 2000; 23:650–657.

20. Ahren B, Larsson H. Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations. Diabetologia. 2001; 44:1998–2003.

21. Rizza RA. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes. 2010; 59:2697–2707.

22. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 1987; 36:274–283.

23. 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.

24. 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; 64:106–110.

25. Raskin P, Unger RH. Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. N Engl J Med. 1978; 299:433–436.

26. Sherwin RS, Fisher M, Hendler R, Felig P. Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects. N Engl J Med. 1976; 294:455–461.

27. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992; 326:22–29.

28. Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 1985; 28:574–578.

29. Del Prato S, Castellino P, Simonson DC, DeFronzo RA. Hyperglucagonemia and insulin-mediated glucose metabolism. J Clin Invest. 1987; 79:547–556.

30. Liljenquist JE, Mueller GL, Cherrington AD, Keller U, Chiasson JL, Perry JM, Lacy WW, Rabinowitz D. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J Clin Invest. 1977; 59:369–374.

31. Brand CL, Jorgensen PN, Knigge U, Warberg J, Svendsen I, Kristensen JS, Holst JJ. Role of glucagon in maintenance of euglycemia in fed and fasted rats. Am J Physiol. 1995; 269(3 Pt 1):E469–E477.

32. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003; 100:1438–1443.

33. Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003; 88:2300–2308.

34. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia. 1983; 24:366–371.

35. Henquin JC, Rahier J. Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia. 2011; 54:1720–1725.

36. Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A. 2010; 107:16009–16012.

37. Matsuda M, Defronzo RA, Glass L, Consoli A, Giordano M, Bressler P, Delprato S. Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism. 2002; 51:1111–1119.

38. Nielsen MF, Wise S, Dinneen SF, Schwenk WF, Basu A, Rizza RA. Assessment of hepatic sensitivity to glucagon in NIDDM: use as a tool to estimate the contribution of the indirect pathway to nocturnal glycogen synthesis. Diabetes. 1997; 46:2007–2016.

39. Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia. 2005; 48:1700–1713.

40. Lund A, Bagger JI, Christensen M, Knop FK, Vilsboll T. Glucagon and type 2 diabetes: the return of the alpha cell. Curr Diab Rep. 2014; 14:555.

41. Unger RH. Role of glucagon in the pathogenesis of diabetes: the status of the controversy. Metabolism. 1978; 27:1691–1709.

42. 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; 85:4053–4059.

43. Bansal P, Wang Q. Insulin as a physiological modulator of glucagon secretion. Am J Physiol Endocrinol Metab. 2008; 295:E751–E761.

44. 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(2 Pt 1):E283–E290.

45. 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.

46. Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, Sewing S, Rorsman P, Braun M. Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes. 2004; 53:1038–1045.

47. Ishihara H, Maechler P, Gjinovci A, Herrera PL, Wollheim CB. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nat Cell Biol. 2003; 5:330–335.

48. Li C, Liu C, Nissim I, Chen J, Chen P, Doliba N, Zhang T, Nissim I, Daikhin Y, Stokes D, Yudkoff M, Bennett MJ, Stanley CA, Matschinsky FM, Naji A. Regulation of glucagon secretion in normal and diabetic human islets by gamma-hydroxybutyrate and glycine. J Biol Chem. 2013; 288:3938–3951.

49. Rorsman P, Salehi SA, Abdulkader F, Braun M, MacDonald PE. K(ATP)-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab. 2008; 19:277–284.

50. Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, Gonzalez A, Groschner LN, Rorsman NJ, Salehi A, Travers ME, Walker JN, Gloyn AL, Gribble F, Johnson PR, Reimann F, Ashcroft FM, Rorsman P. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 2013; 18:871–882.

51. Tschritter O, Stumvoll M, Machicao F, Holzwarth M, Weisser M, Maerker E, Teigeler A, Haring H, Fritsche A. 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; 51:2854–2860.

52. Elder DA, Prigeon RL, Wadwa RP, Dolan LM, D'Alessio DA. Beta-cell function, insulin sensitivity, and glucose tolerance in obese diabetic and nondiabetic adolescents and young adults. J Clin Endocrinol Metab. 2006; 91:185–191.

53. Tfayli H, Bacha F, Gungor N, Arslanian S. Islet cell antibody-positive versus-negative phenotypic type 2 diabetes in youth: does the oral glucose tolerance test distinguish between the two? Diabetes Care. 2010; 33:632–638.

54. Fukuda M, Tanaka A, Tahara Y, Ikegami H, Yamamoto Y, Kumahara Y, Shima K. Correlation between minimal secretory capacity of pancreatic beta-cells and stability of diabetic control. Diabetes. 1988; 37:81–88.

55. 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.

56. Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes. 2002; 51:724–733.

57. Salehi M, D'Alessio DA. Going with the flow: adaptation of beta-cell function to glucose fluxes after bariatric surgery. Diabetes. 2013; 62:3671–3673.

58. Bose M, Teixeira J, Olivan B, Bawa B, Arias S, Machineni S, Pi-Sunyer FX, Scherer PE, Laferrere B. Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery. J Diabetes. 2010; 2:47–55.

59. Camastra S, Muscelli E, Gastaldelli A, Holst JJ, Astiarraga B, Baldi S, Nannipieri M, Ciociaro D, Anselmino M, Mari A, Ferrannini E. Long-term effects of bariatric surgery on meal disposal and beta-cell function in diabetic and nondiabetic patients. Diabetes. 2013; 62:3709–3717.

60. Nannipieri M, Baldi S, Mari A, Colligiani D, Guarino D, Camastra S, Barsotti E, Berta R, Moriconi D, Bellini R, Anselmino M, Ferrannini E. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab. 2013; 98:4391–4399.

61. Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013; 494:256–260.

62. Raskin P, Aydin I, Unger RH. Effect of insulin on the exaggerated glucagon response to arginine stimulation in diabetes mellitus. Diabetes. 1976; 25:227–229.

63. Pfeifer MA, Halter JB, Judzewitsch RG, Beard JC, Best JD, Ward WK, Porte D Jr. Acute and chronic effects of sulfonylurea drugs on pancreatic islet function in man. Diabetes Care. 1984; 7:Suppl 1. 25–34.

64. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015; 38:140–149.

65. Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003; 284:E671–E678.

66. Johnson DG, Goebel CU, Hruby VJ, Bregman MD, Trivedi D. Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science. 1982; 215:1115–1116.

67. Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012; 153:1039–1048.

68. Bagger JI, Knop FK, Holst JJ, Vilsboll T. Glucagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes Metab. 2011; 13:965–971.

69. Russell S. Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. Int J Clin Pharm. 2013; 35:159–172.

70. Irwin N, Franklin ZJ, O'Harte FP. desHis(1)Glu(9)-glucagon-[mPEG] and desHis(1)Glu(9)(Lys(3)(0)PAL)-glucagon: long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity. Eur J Pharmacol. 2013; 709:43–51.

71. O'Harte FP, Franklin ZJ, Rafferty EP, Irwin N. Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists. Mol Cell Endocrinol. 2013; 381:26–34.

72. O'Harte FP, Franklin ZJ, Irwin N. Two novel glucagon receptor antagonists prove effective therapeutic agents in high-fat-fed and obese diabetic mice. Diabetes Obes Metab. 2014; 16:1214–1222.

73. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006; 3:153–165.

74. Gromada J, Rorsman P. New insights into the regulation of glucagon secretion by glucagon-like peptide-1. Horm Metab Res. 2004; 36:822–829.

75. D'Alessio DA, Vogel R, Prigeon R, Laschansky E, Koerker D, Eng J, Ensinck JW. Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest. 1996; 97:133–138.

76. Schirra J, Sturm K, Leicht P, Arnold R, Goke B, Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998; 101:1421–1430.

77. 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.

78. Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996; 19:580–586.

79. 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.

80. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012; 8:728–742.

81. Farngren J, Persson M, Schweizer A, Foley JE, Ahren B. Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes. Diabetes Obes Metab. 2014; 16:812–818.