Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of the increase in UCP2 expression remained unclear. In this study, we investigated the regulatory mechanisms of UCP2 expression and its effects on β-cell functions. The mRNA expression of UCP2 in mouse islets was upregulated by the treatment with glucose, glucokinase activator, or insulin (p<0.05), while metformin downregulated it (p<0.01). Islets from db/db mice and insulin receptor substrate-2 knockout (IRS-2KO) mice showed the increment in the UCP2 expression. Transgenic mouse with specific UCP2 overexpression in β-cells (βUCP2Tg) demonstrated impaired glucose tolerance due to reduced insulin secretion. Adenoviral expression of UCP2 in MIN6-M9 β-cell line also attenuated glucose-induced insulin secretion. The ATP production in response to glucose and mitochondrial Complex I protein level were reduced (p<0.01) in βUCP2Tg islets. Dilatation (1.8-fold, p<0.05) and morphological alteration of mitochondria were observed in βUCP2Tg β-cells. Gene expression microarray analysis revealed 18 upregulated genes (1.5-fold, p<0.05) and 2 downregulated genes (<67%, p<0.05) in βUCP2Tg islets. The most upregulated mRNA by UCP2 expression encoded the aldolase B (Aldob) (77-fold), whose expression was reported to be negatively associated with insulin secretion in human islets (J Clin Endocrinol Metab. 103(12):4373-4383, 2018). We validated increased Aldob expression in islets from βUCP2Tg mice, db/db mice, and IRS-2KO mice. Taken together, UCP2 expression seemed to be increased under T2DM conditions including hyperglycemia or hyperinsulinemia. Our data also suggested that the increase in UCP2 expression in T2DM β-cells cell-autonomously attenuated glucose-induced insulin secretion, possibly via mitochondrial abnormality and Aldob expression.
R. Inoue: None. J. Shirakawa: None. Y. Togashi: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
