MECHANISMS OF INSULIN RESISTANCE IN MAN

人类胰岛素抵抗的机制

基本信息

批准号：
2138267
负责人：
ROBERT A. RIZZA
金额：
$ 29.59万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-05-01 至 1996-08-31
项目状态：
已结题

项目摘要

The goal of therapy of patients with diabetes mellitus is to prevent acute and chronic complications. Until the causes of diabetic complications are known, presumably therapy should attempt to normalize glucose metabolism as well as glucose concentration. Diabetes is associated with alterations in insulin action, insulin secretion, and counterregulatory hormone concentrations. Furthermore, conventional insulin therapy results in systemic rather than portal insulin delivery. The relative contribution of these abnormalities to carbohydrate intolerance in patients with diabetes mellitus is unknown. Since insulin and glucose concentrations continuously change after food ingestion, the rate of onset of insulin action likely is as important as the ultimate response to a given insulin concentration. Initial experiments will validate and use single and dual isotope methods to test the hypotheses that in the presence of euglycemia, rates of insulin induced suppression of hepatic glucose release and stimulation of glucose uptake are similar in nondiabetic man with both being impaired in diabetic man. Efforts also will be made to assess the contribution of gluconeogenesis to persistent hepatic glucose release during hyperinsulinemia. Next, since under physiologic conditions insulin concentrations virtually never increase unless glucose also increases, and since glucose per se is a powerful regulator of glucose metabolism, computerized infusion systems will be used to produce glucose and insulin profiles that mimic those observed in diabetic and nondiabetic patients following food ingestion. The effects of "nondiabetic" and "diabetic" postprandial glucose profiles will be assessed in diabetic and nondiabetic subjects to quantitate the impact of impaired insulin secretion and insulin action on carbohydrate metabolism and to test the hypotheses that following food ingestion, the effects of glucose per se compensate for hepatic insulin resistance in diabetes. In subsequent experiments the regulatory effects and mechanisms by which physiologic changes in glucagon, growth hormone, and cortisol influence postprandial glucose metabolism will be determined by inhibiting and reproducing the normal postprandial suppression of glucagon and nocturnal increases in growth hormone and cortisol. Finally, the ability of systemic insulin delivery to normalize glucose disposition will be examined by comparing postprandial glucose metabolism and insulin action in patients with combined pancreas/kidney transplants to that observed in nondiabetic kidney transplant patients taking the same immunosuppressive agents as well as to that observed in healthy nondiabetic volunteers. By providing a better understanding of the interactions among changes in insulin action, insulin secretion, route of insulin delivery, and the regulatory effects of glucagon, growth hormone, cortisol and glucose per se on glucose metabolism, the proposed experiments hopefully will lead to more rational and effective forms of therapy for people with diabetes mellitus.

糖尿病患者治疗的目的是防止急性和慢性并发症。直到糖尿病的原因并发症已知，大概治疗应该试图正常化葡萄糖代谢以及葡萄糖浓度。糖尿病是与胰岛素作用，胰岛素分泌和反调节激素浓度。此外，传统胰岛素治疗会导致全身而不是门户胰岛素递送。这些异常对碳水化合物的相对贡献糖尿病患者的不耐受是未知的。自胰岛素以来食物摄入后不断变化的葡萄糖浓度，胰岛素作用的发作速率可能与最终一样重要对给定胰岛素浓度的反应。最初的实验将验证并使用单一和双同位素方法来检验假设在存在尤利克血症的情况下，胰岛素诱导的抑制率肝葡萄糖释放和葡萄糖摄取的刺激相似在非糖尿病患者中受损的非糖尿病男子。努力还将进行评估糖异生对高胰岛素血症期间持续的肝葡萄糖释放。接下来，从那以后在生理条件下，胰岛素浓度几乎永远不会除非葡萄糖也增加，否则增加，并且由于葡萄糖本身为a 强大的葡萄糖代谢，计算机输注系统的调节剂将用于产生模仿这些的葡萄糖和胰岛素谱食物摄入后在糖尿病和非糖尿病患者中观察到。 “非糖尿病”和“糖尿病”后葡萄糖特征的影响将在糖尿病和非糖尿病患者中进行评估，以定量胰岛素分泌和胰岛素作用受损对碳水化合物的影响代谢并检验食物摄入后的假设葡萄糖本身的影响补偿了肝胰岛素抵抗糖尿病。在随后的实验中，调节效应和胰高血糖素，生长激素和生理变化的机制皮质醇影响餐后葡萄糖代谢将由抑制和再现正常的餐后抑制胰高血糖素和夜间生长激素和皮质醇的增加。最后，全身胰岛素递送使葡萄糖正常化的能力可以通过比较餐后葡萄糖代谢来检查性格胰腺/肾脏移植的患者的胰岛素作用在非糖尿病肾移植患者中观察到的相同的免疫抑制剂以及在健康中观察到的药物非糖尿病志愿者。通过更好地理解胰岛素作用，胰岛素分泌，途径变化之间的相互作用胰岛素递送和胰高血糖素的调节作用，生长激素，皮质醇和葡萄糖本身在葡萄糖代谢上，提出的希望实验会导致更合理有效的形式糖尿病患者的治疗。