Genetic loss of insulin receptors worsens cardiac efficiency in diabetes.
Genetic loss of insulin receptors worsens cardiac efficiency in diabetes.
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DOI：
10.1016/j.yjmcc.2012.02.001
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发表时间：
2012-05
影响因子：
5
通讯作者：
Abel ED
中科院分区：
文献类型：
--
作者：
Bugger H;Riehle C;Jaishy B;Wende AR;Tuinei J;Chen D;Soto J;Pires KM;Boudina S;Theobald HA;Luptak I;Wayment B;Wang X;Litwin SE;Weimer BC;Abel ED
确定胰岛素信号传导与全身代谢对1型糖尿病心脏代谢和线粒体改变的贡献，并检验先前线粒体功能障碍导致糖尿病心脏效率受损（CE）的假设。用链脲佐菌素（分别为WT-STZ和CIRKO-STZ）使对照小鼠（WT）和具有心肌细胞限制性胰岛素受体缺失的小鼠（CIRKO）患糖尿病，非糖尿病对照接受载体（柠檬酸盐缓冲液）。心功能测定超声心动图;心肌代谢，氧耗量（MVO 2）和CE测定在离体灌注心脏;线粒体功能测定透化心肌纤维和线粒体蛋白质组学液相色谱质谱。丙酮酸支持的呼吸和ATP合成减少糖尿病和基因型，协同损害CIRKO-STZ的ATP合成。与此相反，脂肪酸的输送和利用增加糖尿病无关的基因型，但不是在非糖尿病CIRKO。糖尿病和基因型协同增加CIRKO-STZ的MVO 2，导致CE降低。不考虑糖尿病，基因型受损的ATP/O比值在线粒体暴露于棕榈酰肉碱，符合线粒体解偶联。蛋白质组学显示CIRKO线粒体中脂肪酸氧化蛋白的含量减少，这是由糖尿病引起的，而三羧酸循环和氧化磷酸化蛋白在CIRKO线粒体和糖尿病中均减少。胰岛素信号传导缺陷和糖尿病介导对心肌线粒体的不同影响。当糖尿病被诱导时，胰岛素信号传导的先行损失通过可能继发于线粒体解偶联和增加FA利用的机制显著损害CE。
To determine the contribution of insulin signaling versus systemic metabolism to metabolic and mitochondrial alterations in type 1 diabetic hearts and test the hypothesis that antecedent mitochondrial dysfunction contributes to impaired cardiac efficiency (CE) in diabetes. Control mice (WT) and mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO) were rendered diabetic with streptozotocin (WT-STZ and CIRKO-STZ, respectively), non-diabetic controls received vehicle (citrate buffer). Cardiac function was determined by echocardiography; myocardial metabolism, oxygen consumption (MVO2) and CE were determined in isolated perfused hearts; mitochondrial function was determined in permeabilized cardiac fibers and mitochondrial proteomics by liquid chromatography mass spectrometry. Pyruvate supported respiration and ATP synthesis were equivalently reduced by diabetes and genotype, with synergistic impairment in ATP synthesis in CIRKO-STZ. In contrast, fatty acid delivery and utilization was increased by diabetes irrespective of genotype, but not in non-diabetic CIRKO. Diabetes and genotype synergistically increased MVO2 in CIRKO-STZ, leading to reduced CE. Irrespective of diabetes, genotype impaired ATP/O ratios in mitochondria exposed to palmitoyl carnitine, consistent with mitochondrial uncoupling. Proteomics revealed reduced content of fatty acid oxidation proteins in CIRKO mitochondria, which were induced by diabetes, whereas tricarboxylic acid cycle and oxidative phosphorylation proteins were reduced both in CIRKO mitochondria and by diabetes. Deficient insulin signaling and diabetes mediate distinct effects on cardiac mitochondria. Antecedent loss of insulin signaling markedly impairs CE when diabetes is induced, via mechanisms that may be secondary to mitochondrial uncoupling and increased FA utilization.
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影响因子：
7.7
作者：
Bugger H;Boudina S;Hu XX;Tuinei J;Zaha VG;Theobald HA;Yun UJ;McQueen AP;Wayment B;Litwin SE;Abel ED
通讯作者：
Abel ED
影响因子：
24
作者：
Niemann, Bernd;Chen, Ying;Rohrbach, Susanne
通讯作者：
Rohrbach, Susanne
影响因子：
15.9
作者：
Finck, BN;Lehman, JJ;Kelly, DP
通讯作者：
Kelly, DP
影响因子：
7.7
作者：
Mazumder, PK;O'Neill, BT;Abel, ED
通讯作者：
Abel, ED
影响因子：
8.2
作者：
Li, SY;Yang, X;Ren, J
通讯作者：
Ren, J