ANS HYPOGLYCEMIA INDUCED GLUCAGON SECRETION IN DIABETES

描述(改编自申请人的摘要)： 这项提案中概述的研究将调查四个基本方面 胰高血糖素自主调节的生理学和病理生理学 非糖尿病动物和糖尿病动物模型低血糖期间的分泌 糖尿病。低血糖是一种常见且严重的并发症。 胰岛素治疗的人类糖尿病，限制了 改善血糖控制。糖尿病的控制与并发症 试验发现糖尿病视网膜病变和肾脏病变显著减少 强化治疗，但代价是严重的增加三倍 低血糖症。高血糖素的分泌增加是导致 非糖尿病人中胰岛素诱导的低血糖的恢复。 自主神经系统的激活已经被证明可以使 在低血糖诱导的胰升糖素分泌中的几个重要贡献 然而，包括狗和老鼠在内的物种，自主神经的作用 人类的系统是有争议的，而非人类的这类实验 灵长类动物作为人类生理学的模型，以前还没有进行过。 在糖尿病患者中，胰高血糖素和某些自主神经反应 低血糖通常是受损的。本病的病因和发病时间 对损伤的理解还很少。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 以及自主神经病变。自主神经和胰升糖素对低血糖的反应 在一些糖尿病动物模型中也被认为是受损的，包括 糖尿病大鼠，尽管几乎没有机制研究进行到 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。要解决这些认识上的缺陷 低血糖诱导的胰高血糖素分泌调节：1) 将进行实验，以检验自主神经对 低血糖诱导非人灵长类动物(恒河猴)分泌胰高血糖素 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升糖素分泌受损的研究 在化学诱导(链脲佐菌素)糖尿病的恒河猴中 不同水平的代谢控制对缺陷的影响。3)A类 将在链脲佐菌素糖尿病大鼠身上进行一系列机制研究 研究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 并测定不同治疗方法对胰升糖素分泌的影响 旨在最大限度地提高慢性高血糖或诱发先证者的方案 低血糖，对自主神经反应和胰高血糖素分泌的影响。4)自主性 用链脲佐菌素检测胰升糖素对低血糖的反应 用药物治疗的糖尿病大鼠已被证明可以 改善糖尿病大鼠的神经功能障碍。总而言之，这些 实验将有助于更好地理解病理生理学和 糖尿病患者低血糖逆调节受损的治疗 更多地使用动物模型进行这一领域的调查。

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.