Abstract

Uncoupling protein 2 (UCP2) is a mitochondrial protein, which uncouples the oxidative phosphorylation. UCP2 protein level is reportedly upregulated in pancreatic islets of patients with type 2 diabetes; however, the functional role and mechanism of the upregulated UCP2 remain unclear. In this study, we undertook both in vitro regulation of gene expression and in vivo transgenic approaches to assess the significance of UCP2 in β cells. The expression of UCP2 was significantly upregulated by the stimulation with glucose, glucokinase activator, or insulin in mouse isolated islets (n=3-5, p <0.05). The islet UCP2 expression was also enhanced by the deletion of insulin receptor substrate 2 (IRS-2) (n=3, p <0.05). We generated β-cell-specific UCP2 transgenic (RIP-UCP2) mice, which had 40-fold higher UCP2 expression in islets (n=5, p <0.01), but not in hypothalamus. RIP-UCP2 mice developed glucose intolerance (n=13, p <0.01) in association with tendency to decrease insulin secretion (n=4, p=0.17, at 2 or 5 min after glucose loading), without alterations in insulin sensitivity and β cell mass, compared to the control. ATP/ADP ratio of RIP-UCP2 islets was significantly decreased after glucose stimulation (n=4, p <0.05). Next, we fed mice with high-fat diets (HFD) for 20 weeks. HFD-fed RIP-UCP2 mice initially showed hyperglycemia compared to the control; however, the difference in blood glucose was disappeared after 8 weeks. There were no changes in glucose tolerance, insulin secretion, and insulin sensitivity in HFD-fed RIP-UCP2 mice. β cell mass tended to be increased in HFD-fed RIP-UCP2 mice (1.5-fold compared with HFD-fed control, n=4-5, p=0.15). The IRS-2 expression level was significantly higher in the islets from HFD-fed RIP-UCP2 mice (n=4, p <0.05). Taken together, UCP2 upregulation potentially participates in the reduction in insulin secretion and β cell mass expansion by modulating ATP production and IRS-2 expression. Disclosure R. Inoue: None. J. Shirakawa: None. Y. Togashi: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi & Co., Ltd.. Speaker's Bureau; Self; Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited.

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