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Scientific article
English

Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells

Contributors

Bouzakri, Karim; Ribaux, Pascale Garlonne; Tomas Catala, Alejandra Del Don; Parnaud, Géraldine; Rickenbach, Katharina; Halban, Philippe A.

Published in

Diabetes, vol. 57, no. 5, p. 1195-1204

Publication date

2008

Abstract

OBJECTIVE: Protein kinase B/Akt plays a central role in beta-cells, but little is known regarding downstream Akt substrates in these cells. Recently, Rab GTPase-activating protein 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 fluorescence-activated cell sorted beta-cells and compared in islets from control subjects versus individuals with type 2 diabetes. For knockdown experiments, transformed mouse insulin-secreting MIN6B1 cells were transfected with pSUPER-GFP plasmid encoding a small hairpin RNA against insulin receptor substrate (IRS)-2, AS160, or a negative control. Primary mouse islet cells were transfected with AS160 small interfering RNA. RESULTS: AS160 was expressed in human and mouse pancreatic beta-cells and phosphorylated after glucose stimulation. AS160 mRNA expression was downregulated 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/phosphatidylinositol 3-kinase independently of changes in cytosolic Ca(2+). 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. CONCLUSIONS: 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 protein kinase B/Akt signaling in the beta-cell.

Keywords

  • Animals
  • Apoptosis
  • Cell Division
  • Diabetes Mellitus
  • Type 2/enzymology/genetics
  • Enzyme Activation
  • GTPase-Activating Proteins/genetics/metabolism
  • Gene Expression Regulation Enzymologic
  • Growth Hormone/secretion
  • Humans
  • Insulin-Secreting Cells/cytology/enzymology/pathology/physiology
  • Islets of Langerhans/cytology/enzymology/pathology/physiology
  • Male
  • Mice
  • Mice Inbred C57BL
  • Proto-Oncogene Proteins c-akt/metabolism
  • RNA Interference
  • RNA Messenger/genetics
  • Transfection
  • Rab GTP-Binding Proteins/metabolism

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

BOUZAKRI, Karim et al. Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells. In: Diabetes, 2008, vol. 57, n° 5, p. 1195–1204. doi: 10.2337/db07-1469

Main files (1)

Article (Accepted version)

Identifiers

Additional URL for this publication

http://diabetes.diabetesjournals.org/content/57/5/1195.full.pdf

Journal ISSN

0012-1797
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Technical informations

Creation

19/02/2009 17:32:00

First validation

19/02/2009 17:32:00

Update

26/03/2026 11:10:33

Status update

26/03/2026 11:10:33

Last indexation

26/03/2026 11:11:12
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