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Am J Physiol Endocrinol Metab 291: E982-E994, 2006. First published June 13, 2006; doi:10.1152/ajpendo.00067.2006
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Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis

Laura E. Parton,1 Patrick J. McMillen,2 Yingnian Shen,2 Elizabeth Docherty,2 Erin Sharpe,2 Frédérique Diraison,1 Celia P. Briscoe,3 and Guy A. Rutter1

1Henry Wellcome Signaling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, United Kingdom; and Departments of 2Disease and Biotranscriptomics and 3Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, North Carolina

Submitted 8 February 2006 ; accepted in final form 26 April 2006

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control (fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected (Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca2+ channel subunit {alpha}1D, CPT2, SUR2, rab9, syt13), or inhibited (syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1{alpha} (HNF1{alpha}), HNF3beta/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

pancreatic islets; sterol regulatory element binding protein-1c; glucolipotoxicity


Address for reprint requests and other correspondence: G. A. Rutter, Henry Wellcome Signaling Laboratories and Dept. of Biochemistry, School of Medical Sciences, Univ. Walk, Univ. of Bristol, Bristol BS8 1TD, UK (e-mail: g.a.rutter{at}bris.ac.uk)




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