ANS HYPOGLYCEMIA INDUCED GLUCAGON SECRETION IN DIABETES

描述（改编自申请人摘要）： 这项建议中概述的研究是调查四个基本方面 胰高血糖素自主调节的生理学和病理生理学 在非糖尿病动物和糖尿病动物模型中， 糖尿病 低血压是一种常见而严重的并发症， 胰岛素治疗的糖尿病，这限制了 改善血糖控制。 糖尿病控制和并发症 试验发现糖尿病视网膜病变和肾病的急剧减少， 强化治疗，但代价是严重的 低血糖 胰高血糖素分泌的增加是糖尿病的主要因素。 在非糖尿病人群中从胰岛素诱导的低血糖中恢复。 自主神经系统的激活已被证明可以使 在几种低血糖诱导胰高血糖素分泌中 包括狗和大鼠在内的物种，然而，自主神经的作用 在人类中进行这种系统的实验是有争议的， 灵长类动物作为人类生理学的模型以前没有进行过。 在糖尿病患者中，胰高血糖素和某些自主反应， 低血糖症常常受损。 其病因和发病时间 对损伤的了解很少。 可能涉及的潜在因素 包括但不限于低血糖相关自主神经衰竭 和自主神经病变。 对低血糖的自主神经和胰高血糖素反应 也已知在一些糖尿病动物模型中受损，包括 糖尿病大鼠，尽管很少进行机制研究， 检查潜在的病因，也没有确定是否 药物干预可以预防或减少 反监管缺陷。 为了解决这些理解上的缺陷 低血糖诱导的胰高血糖素分泌的调节：1） 将进行实验以检查自主贡献， 低血糖诱导非人灵长类动物（恒河猴）胰高血糖素分泌 猴子）在没有糖尿病的情况下。 2)确定发病时间 低血糖时自主神经激活和胰高血糖素分泌受损 在患有化学诱导（链脲佐菌素）糖尿病的恒河猴中， 不同水平的代谢控制对赤字的影响。 3)一 本研究将在链脲佐菌素糖尿病大鼠中进行一系列的机制研究 研究是否有自主神经激活缺陷或A细胞减少， 对自主神经刺激的分泌反应可能有助于受损的 胰高血糖素的分泌，并确定不同的治疗效果 方案，旨在最大限度地提高慢性高血糖或诱导前驱 低血糖，对自主反应和胰高血糖素分泌的影响。 4)自主 和胰高血糖素对低血糖症的反应将在链脲佐菌素 用药理学试剂治疗的糖尿病大鼠已经显示， 改善糖尿病大鼠的神经功能障碍。 总的来说，这些 实验将导致对病理生理学的更好理解， 糖尿病中低血糖反调节受损的治疗以及 在这一研究领域更多地使用动物模型。

DESCRIPTION (Adapted from applicant's abstract): The objective of the studies outlined in this proposal is to investigate four fundamental aspects of the physiology and pathophysiology of autonomic regulation of glucagon secretion during hypoglycemia in nondiabetic animals and in animal models of diabetes. Hypoglycemia is a common and serious complication of insulin-treated diabetes mellitus in humans which limits the ability to attain improved glycemic control. The Diabetes Control and Complications Trial found a dramatic decrease of diabetic retinopathy and nephropathy with intensive therapy, but at a cost of a three-fold increase of severe hypoglycemia. Increased secretion of glucagon is a primary factor for recovery from insulin-induced hypoglycemia in nondiabetic humans. Activation of the autonomic nervous system has been demonstrated to make an important contribution to hypoglycemia-induced glucagon secretion in several species including dogs and rats, however, the role of the autonomic nervous system in humans is controversial and experiments of this type in nonhuman primates as models of human physiology have not been previously conducted. In diabetic humans, the glucagon and certain autonomic responses to hypoglycemia are often impaired. The etiology and time of onset of this impairment is poorly understood. Potential factors that may be involved include, but are not limited to, hypoglycemia-associated autonomic failure and autonomic neuropathy. Autonomic and glucagon responses to hypoglycemia are also known to be impaired in some animal models of diabetes, including diabetic rats, although few mechanistic studies have been conducted to examine the underlying etiology, nor has it been determined if pharmacological interventions can to prevent or decrease the counterregulatory defects. To address these deficits in the understanding of t he regulation of hypoglycemia-induced glucagon secretion: 1) Experiments will be conducted to examine the autonomic contribution to hypoglycemia-induced glucagon secretion in a nonhuman primate (rhesus monkeys) in the absence of diabetes. 2) To define the timing of the onset of impaired autonomic activation and glucagon secretion during hypoglycemia in rhesus monkeys with chemically-induced (streptozotocin) diabetes and the effects of different levels of metabolic control on the deficits. 3) A series of mechanistic studies will conducted in streptozotocin diabetic rats to investigate whether defects in of autonomic activation or reduced A-cell secretory responses to autonomic stimulation could contribute to impaired glucagon secretion and to determine the effects of different treatment regimens, designed to maximize chronic hyperglycemia or induce antecedent hypoglycemia, on autonomic responses and glucagon secretion. 4) Autonomic and glucagon responses to hypoglycemia will be examined in streptozotocin diabetic rats treated with pharmacologic agents that have been shown to ameliorate neural dysfunction in diabetic rats. Collectively, these experiments will lead to greater understanding of the pathophysiology and treatment of impaired hypoglycemic counterregulation in diabetes and the greater use of animal models for this area of investigation.