Small G Proteins in Islet β-Cell Function

Glucose-stimulated insulin secretion from the islet -cell involves a sequence of metabolic events and an interplay between a wide range of signaling pathways leading to the generation of second messengers (e.g., cyclic nucleotides, adenine and guanine nucleotides, soluble lipid messengers) and mobilization of calcium ions. Consequent to the generation of necessary signals, the insulin-laden secretory granules are transported from distal sites to the plasma membrane for fusion and release of their cargo into the circulation. The secretory granule transport underlies precise changes in cytoskeletal architecture involving a well-coordinated cross-talk between various signaling proteins, including small molecular mass GTP-binding proteins (G proteins) and their respective effector proteins. The purpose of this article is to provide an overview of current understanding of the identity of small G proteins (e.g., Cdc42, Rac1, and ARF-6) and their corresponding regulatory factors (e.g., GDP/GTP-exchange factors, GDP-dissociation inhibitors) in the pancreatic -cell. Plausible mechanisms underlying regulation of these signaling proteins by insulin secretagogues are also discussed. In addition to their positive modulatory roles, certain small G proteins also contribute to the metabolic dysfunction and demise of the islet -cell seen in in vitro and in vivo models of impaired insulin secretion and diabetes. Emerging evidence also suggests significant insulin secretory abnormalities in small G protein knockout animals, further emphasizing vital roles for these proteins in normal health and function of the islet -cell. Potential significance of these experimental observations from multiple laboratories and possible avenues for future research in this area of islet research are highlighted. (Endocrine Reviews 31: 52-78, 2010) I. Introduction II. The Three Major Classes of G Proteins in Insulin-Secreting -Cells III. Role(s) of Posttranslational Modifications of Small G Proteins in Glucose-Stimulated Insulin Secretion A. G protein prenylation in insulin secretion B. G protein carboxylmethylation in insulin secretion C. G protein palmitoylation/acylation in insulin secretion IV. Regulation of Glucose-Stimulated Insulin Secretion by Small G Proteins A. Cdc42 in insulin secretion B. Rac1 in insulin secretion C. ARF-6 in insulin secretion V. Mechanism(s) of Regulation of Small G Proteins in the Islet -Cell A. Regulation by biologically active lipid second messengers B. Regulation by novel histidine kinases VI. A Model for Potential Cross-Talk between Cdc42, ARF-6, and Rac1 Leading to Glucose-Induced Insulin Secretion VII. A Model for Regulation by Small G Proteins of Glucose-Induced ERK Activation in Insulin Gene Transcription and Insulin Secretion VIII. Regulation of the Metabolic Dysfunction of the Islet -Cell by Small G Proteins A. The Rac1-NADPH oxidase-oxidative stress connection B. Small G proteins in the metabolic dysfunction induced by IL-1 C. Small G proteins in the metabolic dysfunction induced by GTP depletion IX. Insulin Secretory Abnormalities in Small G protein Knockout Animal Models