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.