Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis

1 Henry Wellcome Signaling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, United Kingdom; and Departments of 2 Disease and Biotranscriptomics and 3 Metabolic 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 Ca 2+ channel subunit 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 (HNF1 ), HNF3 /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.ru