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.
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作者：
Bugger H;Boudina S;Hu XX;Tuinei J;Zaha VG;Theobald HA;Yun UJ;McQueen AP;Wayment B;Litwin SE;Abel ED
目的——脂肪酸诱导的线粒体解偶联和氧化应激被认为会降低2型糖尿病患者的心脏效率并导致心功能障碍。我们假设线粒体解偶联也可能导致1型糖尿病秋田小鼠模型的心脏效率降低和收缩功能障碍（Akita）。研究设计和方法：通过超声心动图测定离体工作心脏和体内功能的心脏功能和底物利用率。在皂素渗透纤维中测定了线粒体功能和偶联，在离体线粒体中测定了质子泄漏动力学。在分离的线粒体中测定过氧化氢产量和乌头酸酶活性，在心脏匀浆中测定总活性氧（ROS）。结果：秋田小鼠静息心功能正常，心肌胰岛素敏感性保持正常。虽然秋田大鼠心脏氧化脂肪酸较多，但心肌耗氧量不增加，心肌效率不降低。adp刺激的线粒体耗氧量和ATP合成减少，线粒体形态明显异常。没有氧化应激的证据，尽管解偶联蛋白3 （UCP3）含量增加了两倍，但即使在向秋田心脏灌注1 mmol/l棕榈酸盐后，atp与o的比率和质子泄漏动力学也没有变化。结论：胰岛素缺乏的秋田心脏不表现出脂肪酸诱导的线粒体解偶联，这表明胰岛素反应型1型和胰岛素抵抗型2型糖尿病心脏在线粒体功能障碍的基础上存在重要差异。升高的UCP3水平不会自动增加心脏中的线粒体解偶联，这支持了脂肪酸诱导的线粒体解偶联存在于2型糖尿病心脏中需要同时增加ROS生成的假设。
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.
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