GIP analogues and the treatment of obesity-diabetes

Abstract

The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.