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）：骨骼肌是体内通过葡萄糖摄取、储存为糖原和/或氧化来处理葡萄糖的主要途径。因此，2型糖尿病（T2D）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（T2D）中如何改变。我们将利用我们已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。模型将根据使用纯化线粒体和体内 31P 磁共振波谱的动力学时程实验进行参数化和验证。将从雄性 Wistar 大鼠（血糖正常）和 T2D 的 Goto Kakizaki 大鼠模型（高血糖）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的摄取和处理途径（糖原合成、糖原分解、脂肪酸氧化、TCA 循环和氧化磷酸化）来确定 T2D 中全身葡萄糖处理的变化。我们的目标是定量描述和了解健康和 T2D 动物骨骼肌氧化代谢的调节。此外，彻底了解运动的作用机制、运动影响的假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

Age Reduces Microvascular Function in the Leg Independent of Physical Activity.