Document Detail

Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis.
MedLine Citation:
PMID:  16772326     Owner:  NLM     Status:  MEDLINE    
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 alpha1D, 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-1alpha (HNF1alpha), 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.
Laura E Parton; Patrick J McMillen; Yingnian Shen; Elizabeth Docherty; Erin Sharpe; Frédérique Diraison; Celia P Briscoe; Guy A Rutter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-06-13
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  291     ISSN:  0193-1849     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-10-09     Completed Date:  2006-11-21     Revised Date:  2007-08-13    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E982-94     Citation Subset:  IM    
Henry Wellcome Signaling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.
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MeSH Terms
Blood Glucose / metabolism
Body Weight / physiology
Calcium / metabolism
Gene Expression Profiling*
Insulin / blood*,  secretion
Islets of Langerhans / metabolism*,  secretion
Obesity / genetics*,  metabolism*
Oligonucleotide Array Sequence Analysis
Rats, Zucker
Sterol Regulatory Element Binding Protein 1 / genetics,  metabolism*
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/Blood Glucose; 0/Sterol Regulatory Element Binding Protein 1; 11061-68-0/Insulin; 7440-70-2/Calcium

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