INSULIN RESISTANCE AND HYPERTENSION IN OBESITY

肥胖引起的胰岛素抵抗和高血压

• 批准号: 2229449
• 负责人: Albert P Rocchini
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2229449
• 关键词: antihypertensive agents; atenolol; clonidine; disease /disorder model; dogs; glucose; hypertension; insulin sensitivity /resistance; neuropharmacology; norepinephrine; obesity; prazosin; smooth muscle; striated muscles; sympathetic nervous system; ultrasound blood flow measurement

Recent studies have suggested a link between insulin resistance, increased sympathetic nervous system activity and obesity hypertension. On the basis of our own preliminary data and the human and animal data available in the literature, we hypothesize that central nervous system activation of the sympathetic nervous system maybe responsible for both insulin resistance and hypertension observed in our obese dog model. We should be able to determine what portions of the sympathetic nervous system are responsible for the insulin resistance and hypertension observed in obese dogs, by placing the dogs, before and during the development of obesity, on three different sympathetic agents (clonidine that works centrally, prazosin a peripheral alpha-receptor blocker and atenolol a beta receptor blocker). Insulin mediated glucose uptake is determined both by insulin's ability to stimulate glucose extraction at the level of tissues/cells and by the rate of glucose and insulin's delivery (blood flow). Therefore, the relative contributions of tissue and blood flow actions of insulin will determine the overall rate of glucose uptake (i.e., degree of insulin resistance). In the current proposal we will determine if the insulin resistance associated with obesity in the dog is due to an impairment in insulin's action to increase blood flow and/or to an impairment of insulin to stimulate glucose extraction at the tissue level. We plan to accomplish this specific aim by evaluating the effect of three different insulin infusion levels (euglycemic clamps) to alter regional (leg and cardiac muscular) blood flow (measured by Doppler flow probes) and tissue extraction (arteriovenous difference in glucose). We will also be able to determine how each of the sympathetic agents affects insulin's ability to alter blood flow and the tissue extraction of glucose. Finally we will determine if obesity produces insulin resistance in both skeletal and cardiac muscles. We believe that the results of these experiments will help us to understand why obesity is an important risk factor for the development of both diabetes and cardiovascular disease.

最近的研究表明胰岛素抵抗， 交感神经系统活动增加和肥胖高血压。 根据我们自己的初步数据以及人类和动物的数据， 在文献中，我们假设中枢神经系统 交感神经系统的激活可能是两者的原因 胰岛素抵抗和高血压。 我们应该能够确定交感神经的哪一部分 系统负责胰岛素抵抗和高血压 在肥胖狗中观察到，通过将狗，之前和期间， 肥胖的发展，对三种不同的交感神经药物（可乐定 哌唑嗪是外周α受体阻滞剂， 阿替洛尔，β受体阻滞剂）。 胰岛素介导的葡萄糖摄取是 胰岛素刺激葡萄糖提取的能力， 组织/细胞的水平以及葡萄糖和胰岛素的速率 血流（blood flow）。 因此，组织的相对贡献 胰岛素的血流作用将决定 葡萄糖摄取（即，胰岛素抵抗程度）。 在当前 建议我们将确定是否与胰岛素抵抗相关， 狗的肥胖是由于胰岛素的作用受损， 增加血流量和/或损害胰岛素以刺激 组织水平的葡萄糖提取。 我们计划实现这一目标 通过评估三种不同胰岛素输注的效果， 水平（正常血糖钳夹），以改变局部（腿部和心肌） 血流（通过多普勒血流探头测量）和组织提取 （动静脉葡萄糖差异）。 我们还能确定 每种交感神经药物如何影响胰岛素改变 血液流动和葡萄糖的组织提取。 最后我们将 确定肥胖是否会在骨骼和肌肉中产生胰岛素抵抗， 心肌 我们相信这些实验的结果将 帮助我们理解为什么肥胖是一个重要的风险因素， 糖尿病和心血管疾病的发展。