Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3

Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3 Heiko Bugger 1 , Sihem Boudina 1 , Xiao Xuan Hu 1 , Joseph Tuinei 1 , Vlad G. Zaha 1 , Heather A. Theobald 1 , Ui Jeong Yun 1 , Alfred P. McQueen 2 , Benjamin Wayment 2 , Sheldon E. Litwin 2 and E. Dale Abel 1 1 Division of Endocrinology, Metabolism, and Diabetes and the Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 2 Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah Corresponding author: E. Dale Abel, dale.abel{at}hmbg.utah.edu Abstract OBJECTIVE— Fatty acid–induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita). RESEARCH DESIGN AND METHODS— Cardiac function and substrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates. RESULTS— Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O 2 consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate. CONCLUSIONS— Insulin-deficient Akita hearts do not exhibit fatty acid–induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin-resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in