CARDIAC FUNCTION IN DIABETES EFFECTS OF EXERCISE

运动对糖尿病患者心脏功能的影响

• 批准号: 3463084
• 负责人: DENNIS J PAULSON
• 金额: $ 6.62万
• 依托单位: CHICAGO COLLEGE OF OSTEOPATHIC MEDICINE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3463084
• 关键词: bioenergetics; cardiovascular disorder prevention; coenzyme A; diabetic angiopathy; disease /disorder model; drug related diabetes mellitus; exercise; genetic strain; heart contraction; heart metabolism; insulin dependent diabetes mellitus; laboratory rat; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; perfusion; streptozotocin

It is well established that cardiac contractility is impaired in patients with type I and II diabetes mellitus as well as in experimental animals with genetic or drug-induced diabetes. The mechanism(s), however, for these functional and possibly metabolic defects are unclear. The working hypothesis of this proposal is that exercise training of diabetic animals will improve cardiac contractile performance and metabolism. By determining the metabolic mechanisms through which exercise training improves the function of the diabetic hearts new information about the cause of diabetes-related cardiac dysfunction will be obtained. These studies represent the initial steps toward the long-term goal of preventing the decline in myocardial function that often occurs in diabetic patients, perhaps through moderate exercise training. The effects of chronic diabetes mellitus and exercise training on myocardial contractile performance, energy metabolism and substrate utilization will be assessed in two models of diabetes: the streptozotocin-induced diabetic rat and the genetically obese Zucker rats. The streptozotocin-induced diabetic rats have many of the characteristics of type I diabetes, while the obese Zucker rats are similar to the type II form of diabetes. In all studies, four groups of rats will be investigated: sedentary control, trained control, sedentary diabetic and trained diabetic. For the studies on the streptozotocin-induced diabetic rat a dose of 55 mg/kg, i.v. of streptozotocin will be used and the duration of diabetes will be eight weeks. Treatment of lean and genetically obese Zucker rats will be initiated at 2 months of age and will be continued for 6 months. The effects of diabetes and exercise training on cardiac contractile activity will be studied by measuring in vivo basal myocardial left intraventricular pressure and dP/dt, the responsiveness to i.v. norepinephrine, and by constructing Frank-Starling curves from isolated perfused working hearts. The vulnerability of the isolated perfused heart to global ischemia will also be assessed. Hearts will be perfused with concentrations of glucose and free fatty acids which characterize the in vivo state. Dynamic changes in high energy phosphate metabolites will be measured in Langendorff perfused hearts as a function of aortic perfusion pressure using 31 P-nuclear magnetic resonance spectroscopy. Fatty acid and glucose utilization and tissue content of long-chain acyl carnitine and Co-A esters will also be measured. The metabolic parameters will be correlated to the cardiac contractile activity. Although the metabolic factors that contribute to the functional disturbances that develop in the diabetic heart have not been elucidated unequivocally, abnormal substrate utilization and energy metabolism are implicated as probable sites of action. By reversing of reducing the severity of the metabolic alterations, exercise training may prevent the development of diabetic cardiomyopathy.

众所周知，心肌收缩力受损， I型和II型糖尿病患者以及 患有遗传性或药物诱导的糖尿病的实验动物。 的 然而，这些职能和可能的 代谢缺陷尚不清楚。 这个理论的工作假设是 建议糖尿病动物的运动训练将改善 心脏收缩性能和代谢。 通过确定 运动训练的代谢机制 改善糖尿病心脏功能的新信息 糖尿病相关的心功能障碍的原因 得到了 这些研究代表了迈向 防止心肌功能下降的长期目标 糖尿病患者中经常发生的， 运动训练。 慢性糖尿病与运动训练对糖尿病患者血糖的影响 心肌收缩性能、能量代谢和 将在两种糖尿病模型中评估底物利用： 链脲佐菌素诱导的糖尿病大鼠和遗传性肥胖大鼠 Zucker老鼠 链脲佐菌素诱导的糖尿病大鼠有许多 I型糖尿病的特征，而肥胖的Zucker 大鼠与II型糖尿病相似。 在所有研究中， 将研究四组大鼠：久坐对照， 训练对照组、久坐型糖尿病患者和训练糖尿病患者。 为 链脲佐菌素诱导的糖尿病大鼠的研究 mg/kg，静脉注射链脲佐菌素， 糖尿病将持续8周。 治疗精益和遗传 肥胖Zucker大鼠将在2月龄时开始， 持续了6个月。 糖尿病和运动的影响 心脏收缩活动的训练将由 测量在体基础心肌左心室内压 和dP/dt，对静脉注射去甲肾上腺素的反应性， 从孤立灌注工作构造Frank-Starling曲线 心中 离体灌注心脏对全球性心脏损伤的脆弱性 还将评估局部缺血。 心中充满了 葡萄糖和游离脂肪酸的浓度， 体内状态。 高能磷酸盐的动态变化 将在Langendorff灌注的心脏中测量代谢物， ~（31）P-核磁共振测定主动脉灌注压 共振光谱学 脂肪酸和葡萄糖利用率， 长链酰基肉毒碱和辅酶A酯的组织含量将 也要衡量。 代谢参数将与 心脏收缩活动。 虽然代谢因素 导致大脑中的功能紊乱 糖尿病心脏尚未明确阐明，异常 底物利用和能量代谢， 可能的行动地点。 通过逆转降低 代谢的改变，运动训练可以防止 糖尿病性心肌病的发展。