| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
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 
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
This article has been cited by other articles:
|
|
 |
|
  L. Shu, A. V. Matveyenko, J. Kerr-Conte, J.-H. Cho, C. H.S. McIntosh, and K. Maedler Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function Hum. Mol. Genet., July 1, 2009; 18(13): 2388 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C Cornelis, L. Qi, P. Kraft, and F. B Hu TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women Am. J. Clinical Nutrition, April 1, 2009; 89(4): 1256 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Diraison, M. A. Ravier, S. K. Richards, R. M. Smith, H. Shimano, and G. A. Rutter SREBP1 is required for the induction by glucose of pancreatic {beta}-cell genes involved in glucose sensing J. Lipid Res., April 1, 2008; 49(4): 814 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Shu, N. S. Sauter, F. T. Schulthess, A. V. Matveyenko, J. Oberholzer, and K. Maedler Transcription Factor 7-Like 2 Regulates {beta}-Cell Survival and Function in Human Pancreatic Islets Diabetes, March 1, 2008; 57(3): 645 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. MacDonald and P. Rorsman The Ins and Outs of Secretion from Pancreatic {beta}-Cells: Control of Single-Vesicle Exo- and Endocytosis Physiology, April 1, 2007; 22(2): 113 - 121. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
