AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression in pancreatic islet β-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023–4028]. Using pharmacological and molecular strategies to regulate AMPK activity in rat islets and clonal MIN6 β-cells, we show here that the effects of AMPK are exerted largely upstream of insulin release. Thus forced increases in AMPK activity achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPKα1.T172D), blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK suppressed glucose metabolism, as assessed by changes in total, cytosolic or mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca2+] caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme mutated in the catalytic site (AMPKα1.D157A) did not affect glucose-stimulated increases in [ATP], NAD(P)H or intracellular [Ca2+], but led to the unregulated release of insulin. These results indicate that inhibition of AMPK by glucose is essential for the activation of insulin secretion by the sugar, and may contribute to the transcriptional stimulation of the preproinsulin gene. Modulation of AMPK activity in the β-cell may thus represent a novel therapeutic strategy for the treatment of type 2 diabetes mellitus.
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Research Article|
May 01 2003
Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression
Gabriela da SILVA XAVIER;
Gabriela da SILVA XAVIER
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Isabelle LECLERC;
Isabelle LECLERC
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Aniko VARADI;
Aniko VARADI
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Takashi TSUBOI;
Takashi TSUBOI
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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S. Kelly MOULE;
S. Kelly MOULE
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Guy A. RUTTER
Guy A. RUTTER
1
Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
1To whom correspondence should be addressed (e-mail g.a.rutter@bris.ac.uk).
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Publisher: Portland Press Ltd
Received:
November 20 2002
Revision Received:
February 10 2003
Accepted:
February 17 2003
Accepted Manuscript online:
February 17 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (3): 761–774.
Article history
Received:
November 20 2002
Revision Received:
February 10 2003
Accepted:
February 17 2003
Accepted Manuscript online:
February 17 2003
Citation
Gabriela da SILVA XAVIER, Isabelle LECLERC, Aniko VARADI, Takashi TSUBOI, S. Kelly MOULE, Guy A. RUTTER; Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 1 May 2003; 371 (3): 761–774. doi: https://doi.org/10.1042/bj20021812
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