Effects on pancreatic Beta and other Islet cells of the glucose-dependent insulinotropic polypeptide

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin that, in common with glucagon-like peptide-1 (GLP-1), has both insulin releasing and extra-pancreatic glucoregulatory actions. GIP is released in response to glucose or fat absorption and acts on the GIP receptor (GIPR) to potentiate insulin release from pancreatic beta cells. GIP has also been shown to promote beta cell survival and stimulate the release of GLP-1 from islet alpha cells. There is now evidence to suggest that low levels of GIP are secreted from alpha cells and may act in a paracrine manner to prime neighboring beta cells for insulin release. In addition, GIP acts on adipocytes to stimulate fat storage and can exert anorexigenic effects via actions in the hypothalamus. Contrary to GLP-1, the development of effective GIP-based T2D treatments has been hindered by poor bioavailability and attenuation of beta cell responses to GIP in some patients with sub-optimally controlled T2D. Recently, longer-acting GIP agonists that exhibit enzymatic stability, as well as dual GLP-1/GIP agonists which provide simultaneous improvement in glucose and weight control have been generated and successfully tested in animal T2D models. This, together with reports on GIP antagonists that may protect against obesity, has revived the interest on the GIP/GIPR axis as a potential anti-diabetic pathway. In this review, we summarize the known aspects of the effects of GIP on beta and other islet cells and discuss the most recent developments on GIP-based therapeutic agents for the improvement of beta cell function in T2D patients.