GIP-Based Therapeutics for Diabetes and Obesity

Victor   A.   Gault; Nigel      Irwin; Peter   R.   Flatt

Abstract

Glucose-dependent insulinotropic polypeptide (GIP or gastric inhibitory polypeptide) is a gut-derived incretin hormone which regulates glucose-induced insulin secretion. In addition to its actions on pancreatic beta-cells, GIP exerts a range of secondary extrapancreatic activities, which further augments its antihyperglycaemic properties. As such, GIP has attracted attention as a potential therapeutic agent for the treatment of diabetes, obesity and related metabolic disorders. However, a major drawback in utilising GIP as a therapeutic is its relatively short biological half-life due to degradation by the ubiquitous enzyme dipeptidylpeptidase-IV (DPP-IV) and rapid renal clearance. Consequently, efforts are presently focused on developing more stable and longer-acting forms of GIP which are resistant to DPP-IV-mediated degradation and have improved pharmacokinetic properties. In essence, structural modifications of GIP through N-terminal modification, amino acid substitution and/or fatty acid derivatisation have been shown to generate analogues which exhibit a range of activities from potent agonist action to specific antagonism of native GIP. The purpose of this review is to highlight recent advances in the development of GIP-based therapeutics and their potential in the treatment of type 2 diabetes and obesity.

Keywords: DPP-IV, glucose-dependent insulinotropic polypeptide (GIP), GIP analogues, insulin secretion, obesity, type 2 diabetes

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