TY - JOUR

T1 - Glucagon-like peptide-1

T2 - from extract to agent. The Claude Bernard Lecture, 2005

AU - Holst, Jens Juul

PY - 2006/2

Y1 - 2006/2

N2 - 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.

AB - 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.

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2

KW - Dipeptidyl Peptidase 4

KW - Gastric Inhibitory Polypeptide

KW - Glucagon-Like Peptide 1

KW - Hemoglobin A, Glycosylated

KW - Humans

KW - Hypoglycemic Agents

KW - Injections, Subcutaneous

KW - Insulin

KW - Intestines

KW - Peptides

KW - Protease Inhibitors

KW - Receptors, Glucagon

KW - Venoms

U2 - 10.1007/s00125-005-0107-1

DO - 10.1007/s00125-005-0107-1

M3 - Journal article

C2 - 16416146

VL - 49

SP - 253

EP - 260

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 2

ER -