Glucagon-like peptide-1: From Extract to Agent. The Claude Bernard Lecture, 2005

Diabetologia. 2006 Feb;49(2):253-60. doi: 10.1007/s00125-005-0107-1. Epub 2006 Jan 14.

Abstract

The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA(1)c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA(1)c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptidyl Peptidase 4 / metabolism
  • Exenatide
  • Gastric Inhibitory Polypeptide / metabolism
  • Glucagon-Like Peptide 1* / administration & dosage
  • Glucagon-Like Peptide 1* / analogs & derivatives
  • Glucagon-Like Peptide 1* / therapeutic use
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Injections, Subcutaneous
  • Insulin / metabolism
  • Insulin Secretion
  • Intestines / chemistry
  • Peptides / pharmacology
  • Protease Inhibitors / therapeutic use
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / metabolism
  • Venoms / pharmacology

Substances

  • Blood Glucose
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Protease Inhibitors
  • Receptors, Glucagon
  • Venoms
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Exenatide
  • Dipeptidyl Peptidase 4