A lack of 'glue' misplaces Rab27A to cause islet dysfunction in diabetes

Abstract

Glucose-stimulated insulin secretion (GSIS) involves interplay between metabolic and cationic events. Several lines of evidence suggest novel regulatory roles for small G proteins (Rac1, Cdc42, Rab27A) in cytoskeletal remodelling and docking of insulin granules on the plasma membrane for insulin secretion. Emerging evidence implicates novel roles for post-translational prenylation (farnesylation and geranylgeranylation) of G proteins for their targeting to appropriate membranous compartments. While several recent studies were focused on prenylating enzymes in the islet β-cell, a significant knowledge gap exists on the regulatory roles and function of enzymes that mediate intracellular generation of prenyl pyrophosphate substrates (farnesyl and geranylgeranyl pyrophosphates) for prenyltransferases. Recent work published in The Journal of Pathology by Jiang and associates highlights requisite roles for geranylgeranyl pyrophosphate synthase (GGPPS) in islet β-cell function in health and diabetes. These studies are timely and will form the basis for a series of new investigations to further validate roles for G-protein prenylation in GSIS under physiological conditions. They also pave the path towards the identification of potential defects in these signalling pathways in β-cell models of impaired insulin secretion including metabolic stress and diabetes.