The Two Faces of Protein Palmitoylation in Islet β-Cell Function: Potential Implications in the Pathophysiology of Islet Metabolic Dysregulation and Diabetes

Abiy   M.   Mohammed; Fei      Chen; Anjaneyulu      Kowluru

Abstract

Several cellular proteins undergo post-translational lipidation, including prenylation, palmitoylation and myristoylation, which are felt to promote intracellular targeting, membrane association and interaction with effector partner proteins. Recent findings implicate definitive roles of isoprenylation in islet β-cell function including glucose-stimulated insulin secretion [GSIS]. Published evidence also suggests novel regulatory roles for protein palmitoylation not only in GSIS but also in the metabolic dysfunction induced by proinflammatory cytokines and lipotoxic conditions. Herein, we overviewed the existing evidence on the regulatory roles of protein palmitoylation in the metabolic [dys]regulation of the islet β-cell and highlighted the developments in this area, specifically on potential identity of palmitoylated proteins, and on the utility of two structurally distinct inhibitors of palmitoylation [e.g., cerulenin and 2-bromopalmitate] in halting the metabolic dysfunction of the islet β-cell known to occur following exposure to proinflammatory cytokines and lipotoxic conditions. Potential avenues for future research, including the immediate need for discovery of novel small molecule compounds as inhibitors of palmitoyl transferases to attenuate deleterious consequences of proinflammatory cytokines and glucolipotoxicity are discussed. Furthermore, some relevant patents are also highlighted in this review.

Keywords: 2-Bromo-palmitate, cerulenin, palmitoylation, palmitoyl esterase, palmitoyl transferase, pancreatic β-cells, proinflammatory cytokines, therapeutic targets, type 1 diabetes, and type 2 diabetes.