Mechanisms of Metabolic Dysfunction in Type 2 Diabetes

描述（由申请方提供）：骨骼肌是通过葡萄糖摄取、储存为糖原和/或氧化在体内处理葡萄糖的主要途径。因此，2型糖尿病（T2 D）的发生、发展和治疗与肌肉能量代谢的调节密切相关。我们建议将迭代计算模型与体外和体内实验相结合，以揭示肌肉能量代谢的综合控制，并确定其调节在疾病（T2 D）中如何改变。我们将利用我们已经建立的软件和数据资源的坚实基础，开发肌肉能量代谢的计算机模型。将使用纯化的线粒体和体内31 P-磁共振光谱，基于动力学时程实验对模型进行参数化和验证。将从雄性Wistar大鼠（血糖正常）和T2 D（高血糖）的后藤Kakizaki大鼠模型中获得数据，以确定这些组之间的功能差异。我们将使用建模工作定义的实验方案，通过协调葡萄糖和脂肪酸摄取和处置（糖原合成、糖原分解、脂肪酸氧化、TCA循环和氧化磷酸化）的途径，确定T2 D中全身葡萄糖处置如何改变。我们的目标是定量描述和了解健康和T2 D动物骨骼肌氧化代谢的调节。此外，深入了解运动的作用机制，受运动影响的推定目标可能会产生预防疾病的新方法，并可能确定糖尿病治疗的新靶点。

DESCRIPTION (provided by applicant): Skeletal muscle is the primary pathway of glucose disposal in the body through glucose uptake, storage as glycogen, and/or oxidation. Hence the development, progression and treatment of type 2 diabetes (T2D) are intimately related to the regulation of energy metabolism in muscle. We propose to apply iterative computational modeling in conjunction with both in vitro and in vivo experimentation to uncover the integrated control of energy metabolism in muscle and determine how its regulation is altered in disease (T2D). We will develop computer models of muscle energy metabolism by utilizing the substantial foundation of software and data resources that we have established. Models will be parameterized and validated based on kinetic time- course experiments using purified mitochondria and in vivo 31P-magnetic resonance spectroscopy. Data will be obtained from male Wistar rats (normoglycemic) and the Goto Kakizaki rat model of T2D (hyperglycemic) to identify functional differences between these groups. We will determine how whole body glucose disposal is altered in T2D by coordination of the pathways of glucose and fatty acid uptake and disposal (glycogen synthesis, glycogenolysis, fatty acid oxidation, TCA cycle, and oxidative phosphorylation) using experimental protocols defined by the modeling effort. Our goal is to quantitatively describe and understand the regulation of skeletal muscle oxidative metabolism in both healthy and T2D animals. Furthermore, thorough understanding of the mechanism of action of exercise, the putative targets influenced by exercise may generate new approaches to prevention of the disease and potentially identify new targets for diabetes treatment.