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Transgenic Mice Overexpressing Nuclear SREBP-1c in Pancreatic ß-Cells

¹ Department of Internal Medicine (Metabolism and Endocrinology), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan
² Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. ß-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in ß-cell dysfunction and diabetes.

Abbreviations: CPT, carnitine palmitoyltransferase; FAS, fatty acid synthase; FFA, free fatty acid; GSIS, glucose-stimulated insulin secretion; HFHS, high fat/high sucrose; IGT, impaired glucose tolerance; IRS, insulin receptor substrate; KRBH, Krebs-Ringer bicarbonate buffer with 10 mmol/l HEPES; Nkx6.1, NK6 transcription factor related, locus 1; Pdx, pancreas duodenal homeobox; RIP, rat insulin I promoter; SCD, stealyl CoA desaturase; SREBP, sterol regulatory element-binding protein; UCP, uncoupling protein

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