CARBOHYDRATE METABOLISM AND CATECHOLAMINES

应用程序的长期目标是确定 胰岛素和交感神经系统（SNS）在发病机制中的作用 肥胖相关性高血压具体目标是：1）确定 肥胖高血压患者的交感神经活性水平， 血压正常的肥胖受试者和体重正常的对照者 状态; 2）确定高胰岛素血症（胰岛素 阻力），SNS活动和血压（BP）在人类肥胖相关 建立肥胖相关性高血压大鼠模型 基于高脂肪饮食的长期施用;以及4）确定 胰岛素与SNS、SNS与血压的关系 肥胖相关的高血压在人类受试者中，评估SNS活动 通过测量血浆去甲肾上腺素（NE）浓度、尿NE 排泄， 根据示踪剂计算的NE在循环中的出现率 动力学实验在大鼠中，在心脏、肾脏、 通过测量白色脂肪组织、棕色脂肪组织和肝脏， 在人类和大鼠中，这些器官中的NE周转率 在胰岛素和SNS之间，SNS和BP将由 比较改变胰岛素抵抗和/或 循环胰岛素水平对SNS活性和血压的影响。干预 在人类中使用的包括：蛋白质节约修饰的快速; 用长效生长抑素类似物治疗生长抑素 （奥曲肽，善得定）;正常血糖高胰岛素血症葡萄糖钳夹。 在脂肪喂养的大鼠中，干预措施包括鱼油补充剂;燕麦麸 膳食补充剂;链脲佐菌素诱导的实验性糖尿病;治疗 与奥曲肽。2-脱氧葡萄糖对大鼠交感神经系统的影响 将评估脂肪喂养动物的活动和BP以及肥胖相关 高血压是心血管疾病发病率和死亡率主要原因， 肥胖者虽然高胰岛素血症与高血压有关 心血管风险，胰岛素作用的机制， 影响血压和心血管系统尚未建立。的 本申请中提出的研究将评估 胰岛素介导的交感神经刺激在糖尿病发病机制中的作用 肥胖相关的高血压澄清所涉机制， 重要的治疗意义和潜在的有利影响， 肥胖人群中心血管疾病的发病率。

The long-term goals of the application are to determine the role played by insulin and the sympathetic nervous system (SNS) in the pathogenesis of obesity-relate hypertension. The specific aims are: 1) to determine the level of sympathetic activity in obese hypertensive subjects as compared with obese normotensive subjects and normal weight controls in the ad lib state; 2) to determine the relationships between hyperinsulinemia (insulin resistance), SNS activity, and blood pressure (BP) in human obesity-related hypertension; 3) to develop a rat model of obesity-related hypertension based on the chronic administration of a high fat diet; and 4) to determine the between insulin and the SNS, and the SNS and BP in the rat model of obesity-related hypertension. In human subjects, SNS activity is assessed by measurements of plasma norepinephrine (NE) concentration, urinary NE excretion, and the rate of appearance of NE in the circulation as calculated from tracer kinetic experiments. In rats SNS activity is assessed in heart, kidney, white adipose tissue brown adipose tissue, and liver by the measurement of NE turnover rate in these organs In humans and rats the relationship between insulin and the SNS, and the SNS and BP will determined by comparing the impact of interventions that alter insulin resistance and/or the level of circulating insulin on SNS activity and BP. The intervention utilized include, in humans: a protein sparing modified fast; infusion of somatostatin treatment with a long acting somatostatin analogue (octreotide, Sandostatin); an euglycemic hyperinsulinemic glucose clamps. In fat fed rats the interventions include fish oil supplements; oat bran supplements; experimental diabetes induced by streptozotocin; treatment with octreotide. In rats the effect of 2-deoxyglucose on sympathetic activity and BP in fat fed animals will be assessed as well obesity-related hypertension is a major cause of cardiovascular morbidity and mortality in the obese. Although hyperinsulinemia has been linked with hypertension cardiovascular risk in this group, the mechanisms by which insulin acts to affect BP an the cardiovascular system have not been established. The studies proposed in this application will assess the role of insulin-mediated sympathetic stimulation in the pathogenesis of obesity-related hypertension. Clarification of the mechanisms involved has important therapeutic implications and the potential to impact favorably the cardiovascular morbidity prevalent in the obese.