Skip to main content

Advertisement

SpringerLink
Log in

Gut peptides and type 2 diabetes mellitus treatment

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The gut expresses peptide hormones in endocrine cells and neuropeptides in autonomic nerves. Several of these peptides have the ability to stimulate insulin secretion. Gut hormones that are released after meal ingestion and stimulate insulin secretion postprandially are called incretins. In humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the most important incretins. The potential use of these insulinotropic gut peptides for the treatment of diabetes has been considered. This has been most successful for GLP-1, which exerts antidiabetogenic properties in subjects with type 2 diabetes by stimulating insulin secretion, increasing à-cell mass, inhibiting glucagon secretion, delaying gastric emptying, and inducing satiety. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV), making it unattractive as a therapeutic agent because of a very short half-life. Successful strategies to overcome this difficulty are the use of DPPIV-resistant GLP-1 receptor agonists, such as NN2211 or exendin-4, and the use of inhibitors of DPPIV, such as NVPDPP728 and P32/98. These two approaches are explored in clinical investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Holst JJ, Ørskov C: Incretin hormones-an update. Scand J Clin Lab Invest Suppl 2001, 61:75–85.

    CAS  Google Scholar 

  2. Tseng CC, Kieffer TJ, Jarboe LA, et al.: Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat. J Clin Invest 1996, 98:2440–2445.

    Article  PubMed  CAS  Google Scholar 

  3. Edwards CM, Todd JF, Mahmoudi M, 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.

    Article  PubMed  CAS  Google Scholar 

  4. Miyawaki K, Yamada Y, Yano H, et al.: Glucose intolerance caused by a defect in the enteroinsular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A 1999, 96:14843–14847.

    Article  PubMed  CAS  Google Scholar 

  5. Scrocchi LA, Brown TJ, MaClusky N, et al.: Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 1996, 2:1254–1258.

    Article  PubMed  CAS  Google Scholar 

  6. Vilsbøll T, Krarup T, Deacon CF, et al.: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001, 50:609–613. Shows that the increase in plasma levels of intact GLP-1 after ingestion of a mixed meal is reduced in subjects with type 2 diabetes compared with healthy subjects, whereas the increase in GIP is not different between the two groups.

    Article  PubMed  Google Scholar 

  7. Ahrén B, Larsson H, Holst JJ: Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance. Eur J Endocrinol 1997, 137:127–131.

    Article  PubMed  Google Scholar 

  8. Vaag AA, Holst J, Vølund A, Beck-Nielsen HB: Gut incretin hormones in identical twins discordant for noninsulindependent diabetes mellitus (NIDDM): evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 1996, 135:425–432.

    Article  PubMed  CAS  Google Scholar 

  9. Nauck M, Stockmann F, Ebert R, Creutzfeldt W: Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986, 29:46–52.

    Article  PubMed  CAS  Google Scholar 

  10. Nauck MA, Heimesatt MM, Ørskov C, et al.: Preserved incretin activity of glucagon-like peptide 1 (7-36amide) but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest 1993, 91:301–307.

    PubMed  CAS  Google Scholar 

  11. 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. Illustrates that the ‘early’ insulin response to intravenous glucose is similarly augmented by GIP and GLP-1 in type 2 diabetes as in healthy subjects, whereas the augmentation of the ‘late’ insulin response (20 to 120 minutes) is defective for GIP but normal for GLP-1.

    Article  PubMed  CAS  Google Scholar 

  12. Ahrén B: Glucagon-like peptide 1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes. Bioessays 1998, 20:642–651.

    Article  PubMed  Google Scholar 

  13. Fehmann HC, Göke R, Göke B: Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulinotropic polypeptide. Endocr Rev 1995, 16:390–410.

    Article  PubMed  CAS  Google Scholar 

  14. Drucker DJ: Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002, 122:531–544.

    Article  PubMed  CAS  Google Scholar 

  15. Holst JJ: Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabet Metab Res Rev 2002, 18:430–441.

    Article  CAS  Google Scholar 

  16. Brubaker PL, Schloos J, Drucker DJ: Regulation of glucagonlike peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line. Endocrinology 1998, 139:4108–4114.

    Article  PubMed  CAS  Google Scholar 

  17. Persson K, Gingerich RL, Nayak S, et al.: Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice. Am J Physiol 2000, 279:E956-E962.

    CAS  Google Scholar 

  18. Holst JJ, Deacon CF: Inhibition of the activity of dipeptidylpeptidase IV as a treatment for type 2 diabetes. Diabetes 1998, 47:1663–1670.

    Article  PubMed  CAS  Google Scholar 

  19. Mentlein R: Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides. Regul Pept 1999, 85:9–24.

    Article  PubMed  CAS  Google Scholar 

  20. Kang G, Holz GG: Amplification of exocytosis by Ca2+-induced Ca2+ release in INS-1 pancreatic beta cells. J Physiol 2003, 546:175–189.

    Article  PubMed  CAS  Google Scholar 

  21. Buteay J, Roduit R, Susini S, Prentki M: Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 1999, 42:856–864.

    Article  Google Scholar 

  22. Drucker DJ: Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol 2003, 17:161–171.

    Article  PubMed  CAS  Google Scholar 

  23. Larsson H, Holst JJ, Ahrén B: Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997, 160:413–422.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    PubMed  CAS  Google Scholar 

  25. Verdich C, Flint A, Gutzwiller JP, et al.: A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001, 86:4382–4389.

    Article  PubMed  CAS  Google Scholar 

  26. Ahrén B, Larsson H, Holst JJ: Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997, 82:473–478.

    Article  PubMed  Google Scholar 

  27. Egan JM, Meneilly GS, Habener JF, Elahi D: Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Cin Endocrinol Metab 2002, 87:3768–3673.

    Article  CAS  Google Scholar 

  28. Gutniak M, Ørskov C, Holst J, et al.: Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992, 326:1316–1322. The first study showing that GLP-1 is antidiabetogenic in subjects with diabetes. It studied the effect of intravenously administered GLP-1 on postprandial insulin requirement using an isoglycemic approach with variable rate of insulin infusion.

    Article  PubMed  CAS  Google Scholar 

  29. Juntti-Berggren L, Pigon J, Karpe F, et al.: The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients. Diabetes Care 1996, 19:1200–1206.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Gutniak MK, Larsson H, Sanders SW, et al.: GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care 1997, 20:1874–1879.

    Article  PubMed  CAS  Google Scholar 

  32. 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, 359:824–830. A long-term 6-week study of the antidiabetogenic action of GLP-1 subjects with type 2 diabetes. It shows that fasting and postprandial glucose, as well as HbA1c, are reduced by GLP-1.

    Article  PubMed  CAS  Google Scholar 

  33. Agersø H, Jensen LB, Elbrønd B, et al.: The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002, 45:195–202.

    Article  PubMed  Google Scholar 

  34. Juhl CB, Hollingdal M, Sturis J, et al.: Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002, 51:424–429. Demonstrates the following administration of the GLP-1 analogue, NN2211, at bedtime. Fasting state glucose the following morning is reduced and that following breakfast insulin secretion is augmented, glucagon secretion is reduced, and gastric emptying is delayed, resulting in reduced prandial glycemia.

    Article  PubMed  CAS  Google Scholar 

  35. Greig NH, Holloway HW, De Ore K, et al.: Once-daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 1999, 42:45–50.

    Article  PubMed  CAS  Google Scholar 

  36. Egan JM, Clocquet AR, Elahi D: The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002, 87:1282–1290.

    Article  PubMed  CAS  Google Scholar 

  37. Egan JM, Meneilly GS, Elahi D: Effects of one month bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am J Physiol 2003, 284:E1072-E1079. One-month treatment of subjects with type 2 diabetes with the GLP-receptor agonist, exendin-4, resulted in a reduction in circulating glucose and HbA1c and an increase in insulin secretion.

    CAS  Google Scholar 

  38. Kvist Reimer M, Holst JJ, Ahrén B: Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol 2002, 146:717–727.

    Article  PubMed  Google Scholar 

  39. Popisilik JA, Stafford SG, Demuth HU, et al.: Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 2002, 51:943–950.

    Article  Google Scholar 

  40. Ahrén B, Simonsson E, Larsson H, et al.: Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4 week study period in type 2 diabetes. Diabetes Care 2002, 25:869–875. The first study in subjects with type 2 diabetes using a specific DPPIV inhibitor. Results in the 92 subjects show that during a 4-week study period DPPIV inhibition reduced fasting and postprandial glucose levels as well as HbA1c.

    Article  PubMed  Google Scholar 

  41. Ahrén B, Holst JJ, Yu S: 1,5-Anhydro-D-fructose increases glucose tolerance by increasing GLP-1 and insulin in mice. Eur J Pharmacol 2000, 397:219–225.

    Article  PubMed  Google Scholar 

  42. Larsson H, Ahrén B: Glucose intolerance is predicted by low insulin secretion and high glucagon secretion: outcome of a prospective study in postmenopausal Caucasian women. Diabetologia 2000, 43:194–202.

    Article  PubMed  CAS  Google Scholar 

  43. Meier JJ, Nauck MA, Schmidt WE, Gallwitz B: Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept 2002, 107:1–13.

    Article  PubMed  CAS  Google Scholar 

  44. Holst JJ, Gromada J, Nauck MA: The pathogenesis of NIDDM involves a defective expression of the GIP receptor. Diabetologia 1997, 40:984–986.

    Article  PubMed  CAS  Google Scholar 

  45. Almind K, Ambye L, Urhammar SA, et al.: Discovery of amino acid variants in the human glucose-dependent insulinotropic polypeptide (GIP) receptor: the impact on the pancreatic beta cell responses and functional expression studies in Chinese hamster fibroblast cells. Diabetologia 1998, 41:1194–1198.

    Article  PubMed  CAS  Google Scholar 

  46. O'Harte FP, Mooney MH, Kelley CM, Flatt PR: Improved glycemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide. J Endocrinol 2000, 165:639–648.

    Article  PubMed  Google Scholar 

  47. Karlsson S, Ahrén B: Cholecystokinin and the regulation of insulin secretion. Scand J Gastroenterol 1992, 27:161–165.

    PubMed  CAS  Google Scholar 

  48. Ahrén B, Holst JJ, Efendic S: Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes. J Clin Endocrinol Metab 2000, 85:1043–1048.

    Article  PubMed  Google Scholar 

  49. Filipsson K, Kvist Reimer M, Ahrén B: The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function. Diabetes 2001, 50:1959–1969.

    Article  PubMed  CAS  Google Scholar 

  50. Tsutsumi M, Claus TH, Liang Y, et al.: A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes. Diabetes 2002, 51:1453–1460.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Lund University, B11 BMC, LUND SE-221 84, Sweden

    Bo Ahrén MD, PhD

Authors
  1. Bo Ahrén MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahrén, B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 3, 365–372 (2003). https://doi.org/10.1007/s11892-003-0079-9

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-003-0079-9

Keywords

Search

Navigation