INSULIN RESISTANCE, INCREASED SYMPATHETIC ACTIVITY & OBESITY HYPERTENSION

胰岛素抵抗，交感神经活动增加

• 批准号: 6193131
• 负责人: Albert P Rocchini
• 金额: $ 19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193131
• 关键词: adrenergic agents; antiadrenergic agents; dogs; glucocorticoids; glucose clamp technique; glucose transport; hypertension; insulin sensitivity /resistance; low salt diet; neuropharmacology; nitric oxide; nutrition related tag; obesity; sympathetic nervous system; ultrasound blood flow measurement; vascular resistance; vasomotion

Recent studies in our laboratory along with the work of others have suggested a link between insulin resistance, increased sympathetic nervous system activity and obesity hypertension. We hypothesize that central nervous system activation of the sympathetic nervous system may be responsible for both the 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 four different sympathetic agents (clonidine that works centrally as an alpha2 agonist, moxonidine I1-imidazoline agonist, prazosin a peripheral a alpha1-receptor blocker and atenolol a beta receptor blocker). To better clarify whether a direct and independent relation between blood pressure and insulin resistance exists, we will determine if a low sodium diet plus Lasix will also improve insulin resistance. If our hypothesis is correct, we should observe that since a low sodium diet plus Lasix lowers blood pressure but t the same time activates the sympathetic nervous system, the dogs make fat while on a low sodium diet will remain insulin resistant. 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 delivery (blood flow). Therefore, the relative contributions of tissues 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 actions 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 in dogs made obese are treated with and without sympathetic agents, 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 glucose extraction (arteriovenous difference in glucose). We will evaluate the ability of the central sympathetic agents to alter salt and water retention. Finally we will evaluate what role the sympathetic nervous system plays in the changes in vascular reactivity that occur with obesity. 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.

我们实验室最近的研究沿着其他人的工作表明胰岛素抵抗、交感神经系统活动增加和肥胖高血压之间存在联系。我们推测，中枢神经系统激活交感神经系统可能是负责我们的肥胖狗模型中观察到的胰岛素抵抗和高血压。我们应该能够确定交感神经系统的哪些部分是肥胖犬中观察到的胰岛素抵抗和高血压的原因，方法是在肥胖症发生之前和发生期间，将犬置于四种不同的交感神经药物（作为α 2激动剂的可乐定、莫索尼定I1-咪唑啉激动剂、作为外周α 1受体阻滞剂的哌唑嗪和作为β受体阻滞剂的阿替洛尔）。为了更好地阐明血压和胰岛素抵抗之间是否存在直接和独立的关系，我们将确定低钠饮食加Lasix是否也会改善胰岛素抵抗。如果我们的假设是正确的，我们应该观察到，由于低钠饮食加上Lasix降低血压，但同时激活交感神经系统，狗在低钠饮食时会产生脂肪，从而保持胰岛素抵抗。胰岛素介导的葡萄糖摄取由胰岛素在组织/细胞水平刺激葡萄糖提取的能力以及葡萄糖和胰岛素递送（血流）的速率决定。因此，组织的相对贡献和胰岛素的血流作用将决定葡萄糖摄取的总体速率（即，胰岛素抵抗程度）。在本提案中，我们将确定与犬肥胖相关的胰岛素抵抗是否是由于胰岛素增加血流量的作用受损和/或胰岛素刺激组织水平葡萄糖提取的受损。我们计划通过在使用和不使用交感神经药物治疗的肥胖犬中评价三种不同胰岛素输注水平（正常血糖钳夹）对改变局部（腿部和心肌）血流（通过多普勒血流探头测量）和组织葡萄糖提取（动静脉葡萄糖差异）的影响来实现这一特定目标。我们将评估中枢交感神经药物改变盐和水潴留的能力。最后，我们将评估交感神经系统在肥胖患者血管反应性变化中所起的作用。我们相信这些实验的结果将帮助我们理解为什么肥胖是糖尿病和心血管疾病发展的重要危险因素。