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Role of Uncoupling Protein-2 Up-Regulation and Triglyceride Accumulation in Impaired Glucose-Stimulated Insulin Secretion in a ß-Cell Lipotoxicity Model Overexpressing Sterol Regulatory Element-Binding Protein-1c

Departments of Metabolic Diseases (T.Y., K.E., Y.O., S.Y., T.Y., N.S., T.K.) and Cardiovascular Medicine (R.N.), University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan; CREST of Japan Science and Technology Corp. (K.E., Y.O., T.Y., M.N., T.K.), Saitama 332-0012, Japan; National Institute of Health and Nutrition (M.N., T.K.), Tokyo 162-8636, Japan; and Institute for Diabetes Care and Research, Asahi Life Foundation (M.N.), Tokyo 100-0005, Japan

Address all correspondence and requests for reprints to: Dr. Takashi Kadowaki, Department of Metabolic Diseases, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.

Triglyceride (TG) accumulation in pancreatic ß-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin secretory response to glucose in ß-cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element-binding protein- 1c (SREBP-1c), a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein-2 (UCP-2), which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA for UCP-2 was used. Introduction of the small interfering RNA increased the ATP/ADP ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside, was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to 5-amino-4-imidazolecarboxamide riboside increased free fatty acid oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 down-regulation and AMPK activation could be candidate targets for releasing ß-cells from lipotoxicity.

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