Protein prenylation in islet β-cell function in health and metabolic stress.

Protein prenylation has been implicated in a variety of cellular functions, including cytoskeletal remodeling, trafficking and fusion of secretory vesicles with the plasma membrane. It involves incorporation of either a 15-carbon farnesyl or a 20-carbon geranylgeranyl derivative of mevalonic acid into cysteines at the C-terminus of substrate proteins. At least four types of prenyltransferases, namely farnesyl transferase (FTase) and the geranylgeranyl transferases I-III (GGTase-I, II, and III) have been identified in mammalian cells. Published evidence suggests expression of functionally active forms of these prenyltransferases and their candidate substrate proteins in human islets, rodent islets, and clonal β-cells. Pharmacological and molecular biological evidence implicates requisite roles for protein prenylation in glucose-stimulated insulin secretion. Evidence is also emerging to indicate significant defects in protein prenylome in β-cell models of impaired insulin secretion and diabetes. This review will provide a status update on modulatory roles of protein prenylation, enzymes involved in this signaling pathway, their structural composition and regulation in the context of islet β-cell function in normal health. In addition, experimental evidence on the metabolic fate of protein prenylation pathway in the pancreatic β-cell following chronic exposure to diabetogenic stimuli is reviewed herein. Lastly, crucial gaps in our current understanding, and potential opportunities for future research in this area of islet biology are highlighted.