TI - Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3 . AB - 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 O2 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 the heart , which supports the hypothesis that fatty acid -induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation .