European Journal of Internal Medicine
Volume 20 , Pages S303-S308 , July 2009

Unraveling the Science of Incretin Biology

  • Michael A. Nauck, MD, PhD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Michael A. Nauck, MD, Diabeteszentrum Bad Lauterberg, Kirchberg 21, 37431 Bad Lauterberg im Harz, Germany.

References 

  1. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, D'Agostino RB. Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s. Circulation. 2006;113:2914–2918
  2. Centers for Disease Control and Prevention. Centers for Disease Control National Diabetes Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2007;
  3. The DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care. 2003;26:61–69
  4. International Diabetes Federation. Diabetes Prevalence. International Diabetes Federation, 2007 http://www.idf.org/home/index.cfm?node=6Accessed April 21, 2009
  5. Rydén L, Standl E, Bartnik M, et al. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J. 2007;28:88–136
  6. International Diabetes Federation. Diabetes Atlas. Third Edition. 2006 http://www.eatlas.idf.orgAccessed November 14, 2008
  7. American Diabetes Association. Diabetes Statistics, 2008. American Diabetes Association, 2008 www.diabetes.orgAccessed April 21, 2009
  8. Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. 2006;368:29–36
  9. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy (A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes). Diabetes Care. 2006;29:1963–1972
  10. U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249–1258
  11. Nauck MA. Glucagon-like peptide-1 in type 2 diabetes: the beta cell and beyond. Diabetes Obes Metab. 2008;10(suppl 3):2–13
  12. Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008;168:820–825
  13. Hermansen K, Mortensen LS. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf. 2007;30:1127–1142
  14. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf. 1994;11:223–241
  15. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006;(1):CD002967
  16. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. 2008;31:2086–2091
  17. Barnett AH. The importance of treating cardiometabolic risk factors in patients with type 2 diabetes. Diab Vasc Dis Res. 2008;5:9–14
  18. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004;27:1496–1504
  19. Van Gaal LF, Gutkin SW, Nauck MA. Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitis: glucagon-like agonists or insulin for patients with inadequate glycemic control. Eur J Endocrinol. 2008;158:773–784
  20. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia. 2001;44:929–945
  21. Wajchenberg BL. β-Cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28:187–218
  22. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;51:102–110
  23. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853
  24. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88:787–835
  25. Festa A, Williams K, D'Agostino R, Wagenknecht LE, Haffner SM. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes. 2006;55:1114–1120
  26. Ong KL, Cheung BM, Wong LY, Wat NM, Tan KC, Lam KS. Prevalence, treatment, and control of diagnosed diabetes in the U.S. National Health and Nutrition Examination Survey 1999-2004. Ann Epidemiol. 2008;18:222–229
  27. Horton ES. Can newer therapies delay the progression of type 2 diabetes mellitus?. Endocr Pract. 2008;14:625–638
  28. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443
  29. Nathan DM. Thiazolidinediones for initial treatment of type 2 diabetes?. N Engl J Med. 2006;355:2477–2480
  30. Nauck MA, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52
  31. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157
  32. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940
  33. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705
  34. Nauck MA, Bartels E, Orskov 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;76:912–917
  35. Vilsbøll T, Knop FK, Krarup T, 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;88:4897–4903
  36. Meier JJ, Goetze O, Anstipp J, et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab. 2004;286:E621–E625
  37. 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;9:301–307
  38. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002;45:1111–1119
  39. Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190–S196
  40. Meier JJ, Gallwitz B, Kask B, 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–S224
  41. Eissele R, Goke R, Willemer S, et al. Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest. 1992;22:283–291
  42. Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes. 1994;43:535–539
  43. Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes. 2003;52:124–132
  44. Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetolgia. 2004;47:806–815
  45. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981–E988
  46. Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:2719–2725
  47. Elahi D, McAloon-Dyke M, Fukagawa NK, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regulatory Peptides. 1994;51:63–74
  48. Quddusi S, Vahl TP, Hanson K, Prigeon RL, D'Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003;26:791–798
  49. Byrne MM, Gliem K, Wank U, et al. Glucagon-like peptide 1 improves the ability of the β-cell to sense and respond to glucose in subjects with impaired glucose tolerance. Diabetes. 1998;47:1259–1265
  50. Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide 1 and exendin 4 convert pancreatic AR42J cells into glucagon and insulin-producing cells. Diabetes. 1999;48:2358–2366
  51. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology. 2002;143:3152–3161
  52. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;144:5149–5158
  53. Garber A, Henry R, Ratner R, et al. LEAD-3 (Mono) Study Group Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473–481
  54. Willms B, Werner J, Holst JJ, Ørskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996;81:327–332
  55. Meier JJ, Kemmeries G, Holst JJ, Nauck MA. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes. 2005;54:2212–2218
  56. Näslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord. 1999;23:304–311
  57. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and ß-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830
  58. Nauck MA, Heimesaat MM, Behle K, 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;87:1239–1246
  59. Villanueva-Peñacarrillo ML, Márquez L, González N, Díaz-Miguel M, Valverde I. Effect of GLP-1 on lipid metabolism in human adipocytes. Horm Metab Res. 2001;33:73–77
  60. Knauf C, Cani PD, Perrin C, et al. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005;115:3554–3563
  61. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–151
  62. Nyström T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209–E1215
  63. Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055–3061
  64. Yu M, Moreno C, Hoagland KM, et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003;21:1125–1135
  65. Mudaliar S, Henry RR. Incretin therapies: effects beyond glycemic control. Am J Med. 2009;122(suppl):S25–S36
  66. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–613
  67. Vollmer K, Holst JJ, Baller B, et al. Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes. 2008;57:678–687
  68. Xu G, Kaneto H, Laybutt DR, et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007;56:1551–1558
  69. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care. 1999;22:1137–1143
  70. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91:4612–4619
  71. Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naive patients with Type 2 diabetes. Diabet Med. 2007;24:955–961
  72. Boonacker E, Van Noorden CJ. The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol. 2003;82:53–73
  73. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30:1448–1460
  74. Byetta (exenatide injection) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2008;
  75. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med. 2009;122(suppl):S11–S24

 This article is a copublication with the The American Journal of Medicine, 122, S3-S10. For citation purposes please use European Journal of Internal Medicine, 20, S303-S308.

PII: S0953-6205(09)00095-8

doi: 10.1016/j.ejim.2009.05.012

European Journal of Internal Medicine
Volume 20 , Pages S303-S308 , July 2009