Accumulation of intracellular lipid by pancreatic islet β-cells has been proposed to inhibit normal glucose-regulated insulin secretion (‘glucolipotoxicity’). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for β-cells at the islet periphery. Real-time PCR (TaqMan®) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-γ (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of β-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes.
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March 2004
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Research Article|
March 15 2004
Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)
Frédérique DIRAISON;
Frédérique DIRAISON
*Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Laura PARTON;
Laura PARTON
*Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Pascal FERRÉ;
Pascal FERRÉ
†Unit 465 INSERM, Centre Biomedical des Cordeliers, 15 rue de l'école de médecine, Paris 75270, France
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Fabienne FOUFELLE;
Fabienne FOUFELLE
†Unit 465 INSERM, Centre Biomedical des Cordeliers, 15 rue de l'école de médecine, Paris 75270, France
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Celia P. BRISCOE;
Celia P. BRISCOE
‡Department of Metabolic Diseases, GlaxoSmithKline, 5 Moore Drive Research Triangle Park, NC 27709, U.S.A.
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Isabelle LECLERC;
Isabelle LECLERC
*Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, U.K.
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Guy A. RUTTER
Guy A. RUTTER
1
*Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, 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:
August 21 2003
Revision Received:
November 12 2003
Accepted:
December 22 2003
Accepted Manuscript online:
December 22 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 378 (3): 769–778.
Article history
Received:
August 21 2003
Revision Received:
November 12 2003
Accepted:
December 22 2003
Accepted Manuscript online:
December 22 2003
Citation
Frédérique DIRAISON, Laura PARTON, Pascal FERRÉ, Fabienne FOUFELLE, Celia P. BRISCOE, Isabelle LECLERC, Guy A. RUTTER; Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Biochem J 15 March 2004; 378 (3): 769–778. doi: https://doi.org/10.1042/bj20031277
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