Advertisement

Current Diabetes Reports

, Volume 5, Issue 5, pp 346–352 | Cite as

Utilizing the GLP-1 signaling system to treat diabetes: Sorting through the pharmacologic approaches

  • David A. D’Alessio
  • Torsten P. Vahl
Article

Abstract

cagon-like peptide-1 (GLP-1) is an intestinal hormone that promotes glucose homeostasis through the regulation of insulin and glucagon secretion, gastric emptying, and food intake. This spectrum of effects makes GLP-1 an attractive candidate for drug development. However, because GLP-1 is a small peptide with rapid metabolism in the circulation, its usefulness to treat patients is limited. However, GLP-1 mimetics that are resistant to degradation have been developed and are effective in lowering blood glucose in diabetic patients. A second strategy for harnessing GLP-1 therapeutically is to inhibit the metabolism of endogenous GLP-1; several orally available compounds are in clinical trials. These two new classes of drugs both enhance GLP-1 signaling but differ in several key characteristics that may lead to distinct roles in the treatment of diabetic patients.

Keywords

Metformin Liraglutide Exenatide Gastric Inhibitory Polypeptide Dipeptidyl Peptidase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Kieffer TJ, Habener JF: The glucagon-like peptides. Endocr Rev 1999, 20:876–913.PubMedCrossRefGoogle Scholar
  2. 2.
    D’Alessio DA, Vahl TP: Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab 2004, 286:E882-E890.PubMedCrossRefGoogle Scholar
  3. 3.
    Nauck MA, Heimesaat MM, Orskov C, et al..: Preserved incretin activity of glucagon-like peptide 17-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993, 91:301–307.PubMedGoogle Scholar
  4. 4.
    Elahi D, McAloon-Dyke M, Fukagawa NK, et al.: The insulinotropic actions of glucose-dependent insulinotropic polypeptideGIP) and glucagon-like peptide-17-37) in normal and diabetic subjects. Regul Pept 1994, 51:63–74.PubMedCrossRefGoogle Scholar
  5. 5.
    Rachman J, Gribble FM, Bartow BA, et al.: Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 17-36) amide in patients with NIDDM. Diabetes 1996, 45:1524–1530.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Mentlein R, Gallwitz B, Schmidt WE: Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide,glucagon-like peptide-1(7-36)amide,peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993, 214:829–835.PubMedCrossRefGoogle Scholar
  8. 8.
    Kieffer TJ, McIntosh CHS, Pederson RA: Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995, 136:3585–3596.PubMedCrossRefGoogle Scholar
  9. 9.
    Deacon CF, Johnsen AH, Holst JJ: Degradation of glucagonlike peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995, 80:952–957.PubMedCrossRefGoogle Scholar
  10. 10.
    Vahl TP, Paty BW, Fuller BD, et al.: Effects of GLP-1-(7-36)NH2,LP-1-(7-37),and GLP-19-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab 2003, 88:1772–1779.PubMedCrossRefGoogle Scholar
  11. 11.
    Thorens B: Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A 1992, 89:8641–8645.PubMedCrossRefGoogle Scholar
  12. 12.
    Bullock BP, Heller RS, Habener JF: Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996, 137:2968–2978.PubMedCrossRefGoogle Scholar
  13. 13.
    Nakagawa A, Satake H, Nakabayashi H, et al.: Receptor gene expression of glucagon-like peptide-1, but not glucosedependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 2004, 110:36–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Drucker D, Phillippe J, Mojsov S, et al.: Glucagon-like peptide 1 stimulates insulin gene expression and increases cyclic AMP levels in rat islet cell line. Proc Natl Acad Sci U S A 1987, 84:3434–3438.PubMedCrossRefGoogle Scholar
  15. 15.
    Gromada J, Holst JJ, Rorsman P: Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch 1998, 435:583–594.PubMedCrossRefGoogle Scholar
  16. 16.
    MacDonald PE, El-Kholy W, Riedel MJ, et al.: The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002, 51(suppl 3):S434-S442.PubMedCrossRefGoogle Scholar
  17. 17.
    Kolligs F, Fehmann HC, Goke R, Goke B: Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide. Diabetes 1995, 44:16–19.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    D’Alessio DA, Vogel R, Prigeon R, et al.: 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.PubMedGoogle Scholar
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    Kreymann B, Ghatei MA, Williams G, Bloom SR: Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987, 2:1300–1303.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang Y, Perfetti R, Greig NH, et al.: Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 1997, 99:2883–2889.PubMedGoogle Scholar
  23. 23.
    Xu G, Stoffers DA, Habener JF, Bonner-Weir S: Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999, 48:2270–2276.PubMedCrossRefGoogle Scholar
  24. 24.
    Hardikar AA, Wang XY, Williams LJ, et al.: Functional maturation of fetal porcine beta-cells by glucagon-like peptide 1 and cholecystokinin. Endocrinology 2002, 143:3505–3514.PubMedCrossRefGoogle Scholar
  25. 25.
    Bulotta A, Hui H, Anastasi E, et al.: Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. J Mol Endocrinol 2002, 29:347–360.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang X, Zhou J, Doyle ME, Egan JM: Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic betacells by a cyclic adenosine monophosphate/protein kinase Adependent mechanism. Endocrinology 2001, 142:1820–1827.PubMedCrossRefGoogle Scholar
  27. 27.
    Hvidberg A, Nielsen MT, Hilsted J, et al..: Effect of glucagon-like peptide-1(proglucagon 78-107 amide) on hepatic glucose production in healthy man. Metab Clin Exp 1994, 43:104–108.PubMedGoogle Scholar
  28. 28.
    Creutzfeldt W, Orskov C, Kleine N, et al..: 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Schirra J, Houck P, Wank U, et al.: Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut 2000, 46:622–631.PubMedCrossRefGoogle Scholar
  30. 30.
    Delgado-Aros S, Kim DY, Burton DD, et al.: Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 2002, 282:G424-G431.PubMedGoogle Scholar
  31. 31.
    Schirra J, Wank U, Arnold R, et al.: Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut 2002, 50:341–348.PubMedCrossRefGoogle Scholar
  32. 32.
    Imeryuz N, Yegen BC, Bozkurt A, et al. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 1997,273:G920-G927.PubMedGoogle Scholar
  33. 33.
    Turton MD, O’Shea D, Gunn I, et al..: A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996, 379:69–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Flint A, Raben A, Astrup A, Holst JJ: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998, 101:515–520.PubMedCrossRefGoogle Scholar
  35. 35.
    Vella A, Rizza RA: Extrapancreatic effects of GIP and GLP-1. Horm Metab Res 2004, 36:830–836.PubMedCrossRefGoogle Scholar
  36. 36.
    Nikolaidis LA, Mankad S, Sokos GG, et al.: Effects of glucagonlike peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004, 109:962–965. Describes a small clinical study in which patients having an angioplasty following acute myocardial infarction were treated with 72-hour infusions of recombinant GLP-1. Compared to control subjects with comparable cardiac events that GLP-1 treated, patients had significant improvements in cardiac function. This is the first demonstration of acute effects of GLP-1 on the human heart; it is consistent with animal data suggesting improvement in myocardial metabolism with GLP-1.PubMedCrossRefGoogle Scholar
  37. 37.
    Nauck MA, Kleine N, Orskov C, et al.: Normalization of fasting hyperglycemia by endogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993, 36:741–744.PubMedCrossRefGoogle Scholar
  38. 38.
    Ahren B, Schmitz O: GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. Horm Metab Res 2004, 36:867–876.PubMedCrossRefGoogle Scholar
  39. 39.
    Nielsen LL, Young AA, Parkes DG: Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 2004, 117:77–88.PubMedCrossRefGoogle Scholar
  40. 40.
    Kolterman OG, Kim DD, Shen L, et al..: Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 2005, 62:173–181.PubMedGoogle Scholar
  41. 41.
    Edwards CM, Stanley SA, Davis R, et al.: Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001, 281:E155-E161.PubMedGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    Degn KB, Brock B, Juhl CB, et al.: Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 2004, 53:2397–2403. An excellent clinical study demonstrating that despite increasing insulin secretion rates under basal conditions, exenatide does not affect the coordinated endocrine response to hypoglycemia.PubMedCrossRefGoogle Scholar
  44. 44.
    Kolterman OG, Buse JB, Fineman MS, et al.: Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003, 88:3082–3089.PubMedCrossRefGoogle Scholar
  45. 45.
    Fineman MS, Bicsak TA, Shen LZ, et al..: Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003, 26:2370–2377.PubMedCrossRefGoogle Scholar
  46. 46.
    Buse JB, Henry RR, Han J, et al.: Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004, 27:2628–2635.PubMedCrossRefGoogle Scholar
  47. 47.
    DeFronzo RA, Ratner RE, Han J, et al.: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005, 28:1092–1100.PubMedCrossRefGoogle Scholar
  48. 48.
    Kendall DM, Riddle MC, Rosenstock J, et al.: Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005, 28:1083–1091. The largest of the three pivotal trials conducted with exenatide. The results clearly demonstrate the effects of treatment on long-term glycemic control and body weight and provide a thorough documentation of the type and severity of adverse effects.PubMedCrossRefGoogle Scholar
  49. 49.
    Fineman MS, Shen LZ, Taylor K, et al..: Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes Metab Res Rev 2004, 20:411–417.PubMedCrossRefGoogle Scholar
  50. 50.
    Agerso H, Jensen LB, Elbrond 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.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    Chang AM, Jakobsen G, Sturis J, et al..: The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003, 52:1786–1791.PubMedCrossRefGoogle Scholar
  53. 53.
    Degn KB, Juhl CB, Sturis J, 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, 53:1187–1194. Reports a comprehensive evaluation of the effects of liraglutide on islet function and whole-body glucose metabolism. The results provide a clear picture of the range of effects governed by GLP-1 mimetics.PubMedCrossRefGoogle Scholar
  54. 54.
    Madsbad S, Schmitz O, Ranstam J, et al..: Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagonlike peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004, 27:1335–1342.PubMedCrossRefGoogle Scholar
  55. 55.
    Drucker DJ: Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003, 26:2929–2940.PubMedCrossRefGoogle Scholar
  56. 56.
    Villhauer EB, Brinkman JA, Naderi GB, et al..: 1-[@#@ [(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003, 46:2774–2789.PubMedCrossRefGoogle Scholar
  57. 57.
    Ahren 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.PubMedCrossRefGoogle Scholar
  58. 58.
    Ahren B, Landin-Olsson M, Jansson PA, et al.: Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004, 89:2078–2084.PubMedCrossRefGoogle Scholar
  59. 59.
    Ahren B, Gomis R, Standl E, et al.: Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004, 27:2874–2880. Reports the longest treatment experience to date with a DPP-IV inhibitor. LAF237 reduced hemoglobin A1c significantly and the effect was maintained for 1 year. Over this period, ß-cell function improved with increased insulin release seen despite lower glucose levels.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim D, Wang L, Beconi M, et al.: (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin -7(8H)-yl]-1- (2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005, 48:141–151.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • David A. D’Alessio
    • 1
  • Torsten P. Vahl
    • 1
  1. 1.Division of Endocrinology/MetabolismUniversity of CincinnatiCincinnatiUSA

Personalised recommendations