Mechanisms of Metabolic Dysfunction in Type 2 Diabetes

2 型糖尿病代谢功能障碍的机制

基本信息

批准号：
9033896
负责人：
DANIEL A BEARD
金额：
$ 54.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033896
关键词：
Accounting Acute Affect Animal Model Animals Biochemical Biochemical Process Calcium Carbohydrates Cell Respiration Chronic Citric Acid Cycle Computer Simulation Computer software Cytolysis Data Development Diabetes Mellitus Disease Energy Metabolism Enzymes Exercise Fatty Acids Feedback Foundations Functional disorder Glucose Glycogen Goals Heart Hyperglycemia Impaired fasting glycaemia In Vitro Investigation Kinetics Life Style Magnetic Resonance Spectroscopy Measurement Metabolic Mitochondria Modeling Muscle Muscle Fibers Muscle Mitochondria Myocardium Non-Insulin-Dependent Diabetes Mellitus Oxidative Phosphorylation Oxidoreductase Pathway interactions Phosphorus Phosphorylation Physiological Preparation Prevention approach Process Protocols documentation Rattus Regulation Resources Respiration Rest Site Skeletal Muscle Staging System Testing Therapeutic Intervention Time Treatment Efficacy Wistar Rats Work base biochemical model design diet and exercise drug candidate fatty acid oxidation fatty acid transport glucose disposal glucose uptake glycogenolysis impaired glucose tolerance in vivo inorganic phosphate insight male metabolic abnormality assessment metabolic rate model development novel novel strategies oxidation pyruvate dehydrogenase research study respiratory response simulation uptake

项目摘要

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.

描述（由申请人提供）：骨骼肌是通过葡萄糖摄取，作为糖原和/或氧化的葡萄糖摄取，储存的葡萄糖处置的主要途径。因此，2型糖尿病（T2D）的发育，进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建模与体外和体内实验结合使用，以揭示肌肉中能量代谢的综合控制，并确定其疾病（T2D）的调节如何改变。我们将通过利用我们建立的软件和数据资源的大量基础来开发肌肉能量代谢的计算机模型。使用纯化的线粒体和体内31p-Magnetic共振光谱法基于动力学时间过程实验，将对模型进行参数化和验证。数据将从雄性Wistar大鼠（正常血糖）和T2D的Goto Kakizaki大鼠模型（高血糖）获得，以鉴定这些组之间的功能差异。我们将通过使用模型工作定义的实验方案来确定如何通过协调葡萄糖和脂肪酸摄取和处置的途径（糖原合成，糖基化，脂肪酸氧化，TCA循环和氧化磷酸化），通过使用模型工作定义的实验方案来确定全身葡萄糖处置如何改变T2D。我们的目标是定量描述和了解健康和T2D动物中骨骼肌氧化代谢的调节。此外，对运动作用机理的透彻理解，受运动影响的推定靶标可能会产生预防疾病的新方法，并有可能确定糖尿病治疗的新目标。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes.

在 2 型糖尿病 Goto-Kakizaki 大鼠模型中，骨骼肌能量仅在高强度收缩时才会受到损害。

DOI：
10.1152/ajpregu.00127.2019
发表时间：
2019
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
0
作者：
Lewis,MatthewT;Kasper,JonathanD;Bazil,JasonN;Frisbee,JeffersonC;Wiseman,RobertW
通讯作者：
Wiseman,RobertW

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