PANCREATIC NERVES IN HYPOGLYCEMIA AND EXERCISE

描述（改编自申请人摘要）：本提案的目标 是研究自主神经系统在产生 反调节激素反应，特别是胰高血糖素，以轻度和 中度低血糖以及激素的反应， 正常和糖尿病犬的适度运动。 该信息 具有潜在的临床重要性，因为胰岛素依赖型患者 糖尿病患者的反调节反应减少， 治疗引起的低血糖，有些人容易发生运动引起的低血糖， 低血糖 本提案审查了损害人权的机制， 这种低血糖反应，研究者假设， 糖尿病患者胰腺神经的激活显著有助于 这些问题和这种神经作用的演示可能会影响 他们的治疗方法。 建议的第一部分，具体目标1至3，建议确定 自主输入胰岛刺激胰高血糖素分泌的作用 在低血糖期间。 他们提出去甲肾上腺素溢出的措施 从清醒的狗的胰腺中， 静脉导管，以确认胰腺神经激活在中度 低血糖 他们还提出要检验低血糖 相关的自主神经衰竭（HAAF）通过以下方式损害胰高血糖素反应： 减少非糖尿病狗中这些神经的激活。 他们将 然后研究HAAF在新发糖尿病犬或慢性糖尿病犬中的作用， 严重的高血糖症，在长期的糖尿病狗，假设神经 将发生功能障碍，从而损害胰高血糖素对 低血糖 在具体目标1中，既往低血糖对 将检查胰腺神经的激活， 如果存在自主输入的减少以及这是否与 在非糖尿病狗中胰高血糖素反应受损。 的影响 将检查与低血糖症相对的高胰岛素血症。 此外，本发明还提供了一种方法， 将评价糖皮质激素的作用。 然后是自主神经 第一次低血糖事件引起的激活将被阻断， 随后的损伤是否由这种反应介导。 然后他们将 评估局部胰岛低血糖是否可能介导 HAAF期间的胰高血糖素反应。 在具体目标2中，类似的效果将是 在由四氧嘧啶诱导的新糖尿病犬中进行评价，但特别是 还将评估局部胰岛素缺乏的影响。 具体目标 3、模型将是一只慢性高血糖糖尿病犬， 类似的评价。 此外，慢性高血糖对 外周副交感神经的局部刺激（电） 通路将被检查，自主神经激动剂的作用将被检查。 探讨了 在具体目标4所述提案的第二部分，它们将 记录副交感神经的激活程度， 运动和阻断视网膜神经激活，以量化其在介导 运动诱导的胰岛素减少和胰高血糖素分泌增加。 胰腺去甲肾上腺素溢出和甘丙肽溢出都将是 在正常和慢性糖尿病犬中进行评估。 另外当地 胰腺交感神经递质的释放将被阻断， 为了评估其在胰腺激素反应中的作用， 锻炼的

DESCRIPTION (Adapted from Applicant's Abstract): The goal of this proposal is to investigate the role of the autonomic nervous system in the production of the counterregulatory hormonal response, especially glucagon, to mild and moderate hypoglycemia as well as the response of the hormones during moderate exercise in normal and diabetic dogs. This information is potentially clinically important because patients with insulin-dependent diabetes have decreased counterregulatory responses and poor recovery from treatment-induced hypoglycemia and some are prone to exercise-induced hypoglycemia. This proposal examines the mechanisms for the impairment of this hypoglycemic response and the investigator hypothesizes that impaired activation of pancreatic nerves in diabetics significantly contributes to these problems and that demonstration of such a neural role may influence the approach to their treatment. The first part of the proposal, Specific Aims 1 to 3, propose to determine the role of the autonomic input to the islet to stimulate glucagon secretion during hypoglycemia. They propose the measure the norepinephrine spillover from the pancreas of conscious dogs using chronically implanted pancreatic venous catheters to confirm pancreatic nerve activation during moderate hypoglycemia. They also propose to test the hypothesis that hypoglycemia associated autonomic failure (HAAF) impairs the glucagon response by decreasing the activation of these nerves in non-diabetic dogs. They will then investigate the role of either HAAF in newly diabetic dogs, or chronic severe hyperglycemia, in longer term diabetic dogs assuming that neural disfunction will occur and thereby impaired glucagon response to hypoglycemia. In Specific Aim 1, the effect of prior hypoglycemia on the activation of pancreatic nerves will be examined and it will be determined if there is a reduction of autonomic input and whether this is associated with impaired glucagon responses in non-diabetic dogs. The effect of hyperinsulinemia as opposed to hypoglycemia will be examined. In addition, the effect of glucocorticoids will be evaluated. Then the autonomic activation induced by the first hypoglycemic event will be blocked to assess whether subsequent impairment is mediated by this response. They will then assess whether localized islet hypoglycemia might mediate the impairment of glucagon responses during HAAF. In Specific Aim 2, similar effects will be evaluated in newly diabetic dogs induced by alloxan but in particular the effect of local insulin deficiency will also be evaluated. In Specific Aim 3, the model will be a chronically hyperglycemia diabetic dog undergoing similar evaluation. In addition, the effects of chronic hyperglycemia on the local stimulation (electric) of the peripheral parasympathetic neural pathway will be examined and the effect of autonomic agonists will be explored. In the second part of the proposal described in Specific Aim 4, they will document the degree of activation of the parasympathetic nerves during exercise and block retineural activation to quantify its role in mediating exercise-induced decrease of insulin and increase of glucagon secretion. Both pancreatic norepinephrine spillover and galanin spillover will be evaluated in normal and chronically diabetic dogs. In addition, local pancreatic sympathetic neurotransmitter release will be blocked with bretylium in order to assess its role in the pancreatic hormone response to exercise.