Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes

Islet dysfunction underlies the pathophysiology of type 2 diabetes and is characterized by defective insulin secretion, inappropriately high glucagon secretion and reduced b-cell mass.Several guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are expressed in islet β-cells and contribute to the regulation of islet function, thereby representing potential therapeutic targets.The most important islet incretin hormone GPCRs are glucagon-like peptide 1 (GLP1) receptors and glucose-dependent insulinotropic peptide receptors, which both signal potentiation of glucose-stimulated insulin secretion.GLP1 mimetics and dipeptidyl peptidase 4 inhibitors promote activation of the GLP1 receptors and are currently applied in the treatment of type 2 diabetes.GPR40 and GPR119 are islet lipid GPCRs that signal the potentiation of glucose-stimulated insulin secretion. They are currently being explored as therapeutic targets, particularly because GPR40 and GPR119 agonists also stimulate the release of GLP1 from the gut.Although currently less successful than incretin hormone and lipid GPCRs, other islet GPCRs that are of potential interest as therapeutic targets include the islet pleiotropic GPCRs (glucagon receptors, receptors for pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide, neuropeptide Y receptors, ghrelin receptors and GPR54); the biogenic amine receptors (adrenergic and melatonin receptors); and the muscarinic, endocannabinoid and purinergic receptors.This Review summarizes islet GPCRs expression, signalling and function, and highlights their individual potential as targets for the future treatment of type 2 diabetes.