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Papers In Press, published online ahead of print April 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700533-JLR200

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Journal of Lipid Research, Vol. 49, 814-822, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

SREBP1 is required for the induction by glucose of pancreatic β-cell genes involved in glucose sensing

Frederique Diraison^*, Magalie A. Ravier^*, Sarah K. Richards, Richard M. Smith, Hitoshi Shimano and Guy A. Rutter^1,*

^* Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College, London SW72A2, UK, and Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK
Richard Bright Renal Unit, Southmead Hospital, Bristol BS10 5NB, UK
Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8575, Japan

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three figures.

Published, JLR Papers in Press, January 4, 2008.

¹ To whom correspondence should be addressed. e-mail: g.rutter{at}imperial.ac.uk

Previous studies have reported both positive and negative effects of culture of islets at high glucose concentrations on regulated insulin secretion. Here, we have reexamined this question in mouse islets and determined the role of changes in lipid synthesis in the effects of glucose. Glucose-stimulated insulin secretion (GSIS) and gene expression were examined in islets from C57BL/6 mice or littermates deleted for sterol-regulatory element binding protein-1 (SREBP1) after 4 days of culture at high glucose concentrations. Culture of control islets at 30 versus 8 mmol/l glucose led to enhanced secretion at both basal (3 mmol/l) and stimulatory (17 mmol/l) glucose concentrations and to enhanced triacylglycerol accumulation. These changes were associated with increases in the expression of genes involved in glucose sensing (glucose transporter 2, glucokinase, sulfonylurea receptor 1, inwardly rectifying K⁺ channel 6.2), differentiation (pancreatic duodenal homeobox 1), and lipogenesis (Srebp1, fatty acid synthase, acetyl-coenzyme A carboxylase 1, stearoyl-coenzyme A desaturase 1). When cultured at either 8 or 30 mmol/l glucose, SREBP1-deficient (SREBP1^–/–) islets displayed reduced GSIS and triacylglycerol content compared with normal islets. Correspondingly, glucose induction of the above genes in control islets was no longer observed in SREBP1^–/– mouse islets. We conclude that enhanced lipid synthesis mediated by SREBP1c-dependent genes is required for the adaptive changes in islet gene expression and insulin secretion at high glucose concentrations.

Supplementary key words islets • sterol-regulatory element binding protein-1c • insulin secretion • pancreatic duodenal homeobox 1 • triacsin C

Abbreviations: Abcc8, ATP-binding cassette subfamily C member 8; Acc1, acetyl-coenzyme A carboxylase 1; Chrebp, carbohydrate-responsive element binding protein; ER, endoplasmic reticulum; Fas, fatty acid synthase; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; Gck, glucokinase; GSIS, glucose-stimulated insulin secretion; Kcnj11, inwardly rectifying K⁺ channel 6.2; KRBH, Krebs-Ringer bicarbonate buffer; NKx6.1, NK6 transcription factor locus 1; Pdx1, pancreatic duodenal homeobox 1; Scd1, stearoyl-coenzyme A desaturase 1; Slc2a2, glucose transporter 2; SREBP, sterol-regulatory element binding protein; TG, triglyceride