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M Shimodahira, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
S Fujimoto, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
E Mukai, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y Nakamura, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y Nishi, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
M Sasaki, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y Sato, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
H Sato, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
M Hosokawa, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
K Nagashima, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y Seino, Kansai Electric Power Hospital, Osaka, Japan
N Inagaki, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Shimpei Fujimoto, Email: fujimoto{at}metab.kuhp.kyoto-u.ac.jp

Rapamycin, an immunosuppressant used in human transplantation, impairs β-cell function, but the mechanism is unclear. Chronic (24 h) exposure to rapamycin concentration-dependently suppressed 16.7 mM glucose-induced insulin release from islets (1.65 ± 0.06, 30 nM rapamycin vs. 2.35 ± 0.11 ng/islet/30min, control, n=30, P<0.01) without affecting insulin and DNA contents. Rapamycin also decreased -ketoisocaproate-induced insulin release, suggesting reduced mitochondrial carbohydrate metabolism. ATP content in the presence of 16.7 mM glucose was significantly reduced in rapamycin-treated islets (13.42 ± 0.47, rapamycin vs. 16.04 ± 0.46 pmol/islet, control, n=30, P<0.01). Glucose oxidation, which indicates the velocity of metabolism in the Krebs cycle, was decreased by rapamycin in the presence of 16.7 mM glucose (30.1 ± 2.7, rapamycin vs. 42.2 ± 3.3 pmol/islet/90min, control, n=9, P<0.01). Immunoblotting revealed that the expression of complex I, III, IV, and V was not affected by rapamycin. Mitochondrial ATP production indicated that the respiratory chain downstream of complex II was not affected but that carbohydrate metabolism in the Krebs cycle was reduced by rapamycin. Analysis of enzymes in the Krebs cycle revealed that activity of -ketoglutarate dehydrogenase, which catalyzes one of the slowest reactions in the Krebs cycle, was reduced by rapamycin (10.08 ± 0.82, rapamycin vs. 13.82 ± 0.84 nmol/mg mitochondrial protein/min, control, n=5, P<0.01). Considered together, these findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced -ketoglutarate dehydrogenase activity.