Small G Proteins in Islet β-Cell Function

Abstract

Glucose-stimulated insulin secretion from the islet beta-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 beta-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 beta-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 beta-cell. Potential significance of these experimental observations from multiple laboratories and possible avenues for future research in this area of islet research are highlighted.

Cadherin Engagement Improves Insulin Secretion of Single Human β-Cells

“…Indeed, final access of secretory granules to the plasma membrane requires dissolution of a defined cortical actin web. Recent reports have underlined a possible role for the Rho-GTPases (44,47,48) in cortical F-actin reorganization during regulated insulin secretion.…”

Biphasic Roles of a Small G-Protein, RAC1 in Pancreatic Β-Cell

“…49 These Rab GTPases assists in priming and docking of insulinladen secretory granules on the plasma membrane. Unlike first category of small G-proteins, requisite for posttranslational modifications and mechanism[s] involved in the activation of Rab GTPases under the physiological insulin secretagogues remains elusive.…”

“…Any imbalance in either of the regulatory factors alters the hydrolytic cycle and physiological functions in pancreatic β-cells. 49,57,58 …”

“…19, 49 In addition, Rac1 has also been shown to play a vital role in various diseased states including cancer and neurological disorders, [60][61][62] liver fibrosis 63 and diabetes. 57,58 Furthermore, Rac1 protein has shown to be associated with GLUT4 translocation in the muscle of diabetic patients.…”

Regulation of glucose- and mitochondrial fuel-induced insulin secretion by a cytosolic protein histidine phosphatase in pancreatic β-cells

“…Previous studies from multiple laboratories have suggested regulatory roles for both heterotrimeric and small molecular mass G proteins in GSIS (26). In addition, Mas, a tetradecapeptide from wasp venom, has been shown to elicit direct stimulatory effects on protein histidine phosphorylation, G protein activation, and insulin secretion (11,20,25,26) in a variety of insulin-secreting cells. Therefore, we next determined potential regulatory roles for PHP in Mas-induced insulin secretion from INS 832/13 cells.…”