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Diabetes Publish Ahead of Print published online ahead of print February 14, 2008
DOI: 10.2337/db07-1469
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Original Research

Rab-GAP AS160 is a major downstream effector of PKB/Akt signaling in pancreatic beta-cells

Karim Bouzakri1, Pascale Ribaux1, Alejandra Tomas1, Geraldine Parnaud1, Katharina Rickenbach1, and Philippe A. Halban1

1From the Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland

Objective: PKB/Akt plays a central role in beta-cells but little is known regarding downstream Akt substrates in these cells. Recently, Rab-GAP AS160, a substrate of Akt was shown to be involved in insulin modulation of GLUT4 trafficking in skeletal muscle and adipose tissue. The aim of this study was to investigate the expression and potential role of AS160 in beta-cells.

Research Design and Methods: AS160 mRNA expression was measured in mouse and human islets and (FACS) sorted beta cells, and compared in islets from control vs. individuals with type 2 diabetes. For knockdown experiments, transformed mouse insulin secreting MIN6B1 cells were transfected with pSUPER-GFP plasmid encoding a shRNA against IRS-2, AS160 or a negative control. Primary mouse islet cells were transfected with AS160 siRNA.

Results: AS160 was expressed in human and mouse pancreatic beta-cells and phosphorylated after glucose stimulation. AS160 mRNA expression was down-regulated in pancreatic islets from individuals with type 2 diabetes. In MIN6B1 cells, glucose induced phosphorylation of Akt and AS160 and this was mediated by insulin receptor/IRS-2/PI3-Kinase, independently of changes in cytosolic Ca2+. Knockdown of AS160 resulted in increased basal insulin secretion whereas glucose-stimulated insulin release was abolished. Furthermore, beta-cells with decreased AS160 showed increased apoptosis and loss of glucose-induced proliferation.

Conclusion: This study shows for the first time that AS160, previously recognized as a key player in insulin signaling in skeletal muscle and adipose tissue, is also a major effector of PKB/Akt signaling in the beta-cell.

Correspondence: karim.bouzakri{at}medecine.unige.ch


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