Die Rolle der Insulinresistenz bei der Entwicklung einer Herzinsuffizienz- Molekulare Signalwege und der Einfluss des Energiesubstratstoffwechsels

胰岛素抵抗（IR）是心力衰竭（HF）的危险因素。全身性IR通常与肥胖和糖尿病（T2DM）有关。心脏IR可能是慢性全身IR的结果。我们还证实了压力过载HF大鼠的心脏IR。心肌IR发生于线粒体功能障碍发生之前，后者与收缩功能障碍有关。在T2DM小鼠中发现了IR和线粒体功能障碍之间的因果关系。在正常情况下，胰岛素对线粒体功能具有“细胞维持”作用。它刺激线粒体的生物发生，促进了一个片断枯竭的克雷布斯循环（逆转）的补充。我们假设IR加速，而逆转IR延迟或防止压力过载HF的发生。我们认为心脏IR通过线粒体功能障碍的发展触发HF。我们将对有或没有IR的小鼠（db/db, ob/ob, NSCL-2-/-）进行主动脉收缩，并评估体内和离体收缩功能、底物利用率和线粒体功能（Specific Aim 1）。我们将在体内和细胞培养中探讨潜在的信号机制（包括shRNA敲低，Specific Aim 2）。结果可能为治疗心衰提供一种新的但易于应用的方法。

Insulin resistance (IR) is a risk factor for heart failure (HF). Systemic IR is usually associated with obesity and diabetes mellitus (T2DM). Cardiac IR may develop as a consequence of chronic systemic IR. We also demonstrated cardiac IR in rats developing pressure overload HF. Here cardiac IR developed before the onset of mitochondrial dysfunction, the latter being associated with contractile dysfunction. A causal link between IR and mitochondrial dysfunction was found in mice with T2DM. Under normal conditions, insulin has a “cellular maintenance” effect on mitochondrial function. It stimulates mitochondrial biogenesis and facilitates replenishment of a moiety-depleted Krebs-cycle (anaplerosis). We hypothesize that IR accelerates and that reversing IR delays or prevents the onset of pressure overload HF. We propose that the onset of cardiac IR triggers HF through the development of mitochondrial dysfunction. We will perform aortic constriction in mice with or without IR (db/db, ob/ob, NSCL-2-/-) and assess contractile function in and ex vivo, substrate utilization rates and mitochondrial function (Specific Aim 1). We will address the underlying signaling mechanisms in vivo and in cell culture (incl. shRNA knockdown, Specific Aim 2).The results may provide a new but readily applicable approach to treat HF.