Alpha cell function in type 1 diabetes

Authors

  • David Simon Hughes Centre of Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
  • Parth Narendran Centre of Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

DOI:

https://doi.org/10.15277/bjdvd.2014.014

Abstract

Our understanding of the pathogenesis of type 1 diabetes mellitus has traditionally revolved around the insulin deficiency that follows pancreatic beta cell loss. However, there is an increasing appreciation of defects in other gluco-regulatory cells in type 1 diabetes mellitus. Oversecretion of glucagon from pancreatic alpha cells is characteristic of type 1 diabetes mellitus, and modulating these glucagon levels reduces hyperglycaemia. This article reviews alpha cell function in type 1 diabetes mellitus. We examine how its function is controlled and compromised, and review studies that target alpha cell function. Finally, we explore potential approaches to modulating alpha cell function in type 1 diabetes mellitus.

References

Doyle MJ, Loomis ZL, Sussel L. Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. Development 2007;134:515-23. http://dx.doi.org/10.1242/dev.02763

Lane M. The cytological characters of the areas of Langerhans. Am J Anat 1907;7:409-22. http://dx.doi.org/10.1002/aja.1000070304

Kimball CP, Murlin JR. Aqueous extracts of pancreas. J Biol Chem 1923;58:337–48.

Dunphy JL, Taylor RG, Fuller PJ. Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expression. Mol Cell Endocrinol 1998;141:179-86. http://dx.doi.org/10.1016/S0303-7207(98)00096-3

Tucker JD, Dhanvantari S, Brubaker PL. Proglucagon processing in islet and intestinal cell lines. Regul Pept 1996;62:29-35. http://dx.doi.org/10.1016/0167-0115(95)00167-0

Llewellyn-Smith IJ, Reimann F, Gribble FM, et al. Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience 2011;180:111-21. http://dx.doi.org/10.1016/j.neuroscience.2011.02.023

Nie Y, Nakashima M, Brubaker PL, et al. Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J Clin Invest 2000;105:955-65. http://dx.doi.org/10.1172/JCI7456

Vieira E, Salehi a, Gylfe E. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 2007;50:370-9. http://dx.doi.org/10.1007/s00125-006-0511-1

Rorsman P, Salehi SA, Abdulkader F, et al. K(ATP)-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab 2008;19:277-84. http://dx.doi.org/10.1016/j.tem.2008.07.003

Quesada I, Tudurí E, Ripoll C, et al. Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 2008;199:5-19. http://dx.doi.org/10.1677/JOE-08-0290

Ekblad E, Sundler F. Distribution of pancreatic polypeptide and peptide YY. Peptides 2002;23:251-61. http://dx.doi.org/10.1016/S0196-9781(01)00601-5

Andralojc KM, Mercalli A, Nowak KW, et al. Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia 2009;52:486-93. http://dx.doi.org/10.1007/s00125-008-1238-y

Whalley NM, Pritchard LE, Smith DM, et al. Processing of proglucagon to GLP-1 in pancreatic {alpha}-cells: is this a paracrine mechanism enabling GLP-1 to act on {beta}-cells? J Endocrinol 2011;211:99-106. http://dx.doi.org/10.1530/JOE-11-0094

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. http://dx.doi.org/10.1210/er.2006-0007

Kumar U, Sasi R, Suresh S, et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes 1999; 48:77-85. http://dx.doi.org/10.2337/diabetes.48.1.77

Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev 2005;21:91-117. http://dx.doi.org/10.1002/dmrr.538

Parker HE, Habib AM, Rogers GJ, et al. Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 2009;52:289-98. http://dx.doi.org/10.1007/s00125-008-1202-x

Meier JJ, Gallwitz B, Siepmann N, et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 2003;46:798-801. http://dx.doi.org/10.1007/s00125-003-1103-y

Tudurí E, Marroquí L, Soriano S, et al. Inhibitory effects of leptin on pancreatic alpha-cell function. Diabetes 2009;58:1616–24. http://dx.doi.org/10.2337/db08-1787

Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379-406. http://dx.doi.org/10.1152/physrev.90100.2007

Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 2011;17:1481-9. http://dx.doi.org/10.1038/nm.2513

Ahrén B. Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia 2000;43:393-410. http://dx.doi.org/10.1007/s001250051322

Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358:221-9. http://dx.doi.org/10.1016/S0140-6736(01)05415-0

Thorel F, Népote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010;464:1149-54. http://dx.doi.org/10.1038/nature08894

Lee Y, Wang M-Y, Du XQ, et al. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 2011;60:391-7. http://dx.doi.org/10.2337/db10-0426

Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 2003;100:1438-43. http://dx.doi.org/10.1073/pnas.0237106100

Parker JC, Andrews KM, Allen MR, et al. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun 2002;290:839-43. http://dx.doi.org/10.1006/bbrc.2001.6265

Brand CL, Rolin B, Jørgensen PN, et al. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 1994;37:985-93. http://dx.doi.org/10.1007/BF00400461

Raskin P, Unger RH. Effect of insulin therapy on the profiles of plasma immunoreactive glucagon in juvenile-type and adult-type diabetics. Diabetes 1978;27:411-19. http://dx.doi.org/10.2337/diab.27.4.411

Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care 2008;31:1403-04. http://dx.doi.org/10.2337/dc08-0575

Cooperberg BA, Cryer PE. Beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans. Diabetes Care 2009;32:2275-80. http://dx.doi.org/10.2337/dc09-0798

Pörksen S, Nielsen LB, Kaas A, et al. Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. J Clin Endocrinol Metab 2007;92:2910–16. http://dx.doi.org/10.1210/jc.2007-0244

Lindgren O, Carr RD, Deacon CF, et al. Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. J Clin Endocrinol Metab 2011;96:2519-24. http://dx.doi.org/10.1210/jc.2011-0266

Meier JJ, Deacon CF, Schmidt WE, et al. Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects. Diabetologia 2007;50:806-13. http://dx.doi.org/10.1007/s00125-007-0598-z

Hare KJ, Vilsbøll T, Holst JJ, et al. 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. http://dx.doi.org/10.1152/ajpendo.00700.2009

Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology 2012;153:1039-48. http://dx.doi.org/10.1210/en.2011-1499

Abdul-Ghani M, DeFronzo RA. Fasting hyperglycemia impairs glucose- but not insulin-mediated suppression of glucagon secretion. J Clin Endocrinol Metab 2007;92:1778-84. http://dx.doi.org/10.1210/jc.2006-1515

Greenbaum CJ, Prigeon RL, D’Alessio DA. Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 2002;51:951-7. http://dx.doi.org/10.2337/diabetes.51.4.951

Siafarikas A, Johnston RJ, Bulsara MK, et al. Early loss of the glucagon response to hypoglycemia in adolescents with Type 1 diabetes. Diabetes Care 2012;35(8):1757-62. http://dx.doi.org/10.2337/dc11-2010

Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest 1993;91:819-28. http://dx.doi.org/10.1172/JCI116302

Lorenzi M, Bohannon N, Tsalikian E, et al. Duration of type I diabetes affects glucagon and glucose responses to insulin-induced hypoglycemia. West J Med 1984;141:467-71.

Fukuda M, Tanaka A, Tahara Y, et al. Correlation between minimal secretory capacity of pancreatic beta-cells and stability of diabetic control. Diabetes 1988;37:81-8. http://dx.doi.org/10.2337/diab.37.1.81

Meier JJ, Gethmann A, Götze O, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 2006;49:452-8. http://dx.doi.org/10.1007/s00125-005-0126-y

Varanasi A, Bellini N, Rawal D, et al. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 2011;165:77-84. http://dx.doi.org/10.1530/EJE-11-0330

Kielgast U, Krarup T, Holst JJ, et al. 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;34:1463-8. http://dx.doi.org/10.2337/dc11-0096

Raman VS, Mason KJ, Rodriguez LM, et al. The role of adjunctive exenatide therapy in pediatric type 1 diabetes. Diabetes Care 2010; 33:1294-6. http://dx.doi.org/10.2337/dc09-1959

Garg SK, Moser EG, Bode B, et al. Effect of Sitagliptin on post-prandial glucagon and GLP-1 levels in patients with type 1 diabetes: Investigator-initiated, double-blind, randomized, placebo-controlled trial. Endocr Pract 2012;:1–30.

Farngren J, Persson M, Schweizer A, et al. Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in Type 1 diabetes. J Clin Endocrinol Metab 2012;97:1-8. http://dx.doi.org/10.1210/jc.2012-2332

Ellis SL, Moser EG, Snell-Bergeon JK, et al. Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 2011;28:1176-81. http://dx.doi.org/10.1111/j.1464-5491.2011.03331.x

Foley JE, Ligueros-Saylan M, He Y-L, et al. Effect of vildagliptin on glucagon concentration during meals in patients with type 1 diabetes. Horm Metab Res 2008;40:727-30. http://dx.doi.org/10.1055/s-2008-1078754

Chase HP, Lutz K, Pencek R, et al. Pramlintide lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study. J Pediatr 2009;155:369-73. http://dx.doi.org/10.1016/j.jpeds.2009.03.012

Edelman S, Garg S, Frias J, et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 2006;29:2189-95. http://dx.doi.org/10.2337/dc06-0042

Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 2004;21:1204-12. http://dx.doi.org/10.1111/j.1464-5491.2004.01319.x

Levetan C, Want LL, Weyer C, et al. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003;26:1-8. http://dx.doi.org/10.2337/diacare.26.1.1

Whitehouse F, Kruger DF, Fineman M, et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002;25:724–30. http://dx.doi.org/10.2337/diacare.25.4.724

Flatt PR, Swanston-Flatt SK, Bailey CJ. Glucagon antiserum: a tool to investigate the role of circulating glucagon in obese-hyperglycaemic (ob/ob) mice. Biochem Soc Trans 1979;7:911-13.

Yan H, Gu W, Yang J, et al. Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys. J Pharmacol Exp Ther 2009;329:102-11. http://dx.doi.org/10.1124/jpet.108.147009

Gu W, Yan H, Winters KA, et al. Long-term inhibition of the glucagon receptor with a monoclonal antibody in mice causes sustained improvement in glycemic control, with reversible alpha-cell hyperplasia and hyperglucagonemia. J Pharmacol Exp Ther 2009;331:871-81. http://dx.doi.org/10.1124/jpet.109.157685

Engel SS, Xu L, Andryuk PJ, Davies MJ, Amatruda J, Kaufman K GB. Efficacy and tolerability of MK-0893, a glucagon receptor antagonist, in patients with type 2 diabetes. Diabetes 2011;60:A85

Kelly RP, Garhyan P, Abu-Raddad EJ, Fu H, Lim CN, Prince MJ, Pinaire JA, Loh MT DM. Short-term treatment with glucagon receptor antagonist LY2409021 effectively reduces fasting blood glucose and HbA1c in patients with type 2 diabetes mellitus. Diabetes 2011;60:A84.

Ali S, Drucker DJ. Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes. Am J Physiol Endocrinol Metab 2009;296:E415–21. http://dx.doi.org/10.1152/ajpendo.90887.2008

Claus TH, Pan CQ, Buxton JM, et al. Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes. J Endocrinol 2007;192:371-80. http://dx.doi.org/10.1677/JOE-06-0018

Fortin J-P, Chinnapen D, Beinborn M, et al. Discovery of dual-action membrane-anchored modulators of incretin receptors. PLoS One 2011;6:e24693. http://dx.doi.org/10.1371/journal.pone.0024693

Bhat VK, Kerr BD, Flatt PR, et al. A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties. Biochem Pharmacol 2013; 85:1655-62. http://dx.doi.org/10.1016/j.bcp.2013.03.009

Nass R, Gaylinn BD, Thorner MO. The ghrelin axis in disease: potential therapeutic indications. Mol Cell Endocrinol 2011;340:106-10. http://dx.doi.org/10.1016/j.mce.2011.02.010

Denroche HC, Levi J, Wideman RD, et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 2011;60:1414-23. http://dx.doi.org/10.2337/db10-0958

Garg A. Effects of metreleptin in Type 1 diabetes mellitus. clinicaltrials.gov. 2010;:NCT01268644.

Ansarullah, Lu Y, Holstein M, et al. Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor. PLoS One 2013;8:e53345. http://dx.doi.org/10.1371/journal.pone.0053345

Ogata A, Morishima A, Hirano T, et al. Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis 2011;70:1164-5. http://dx.doi.org/10.1136/ard.2010.132845

Downloads

Published

2014-06-09

Issue

Vol. 14 No. 2 (2014)

Section

Reviews

License

Publish & Transfer of Copyright Agreement
For the mutual benefit and protection of the Author and the Journal Owner/Publisher it is necessary that the Author provides formal written Consent to Publish and Transfer of Copyright before publication of the Work.

Most read articles by the same author(s)