PANCREATIC NERVES IN HYPOGLYCEMIA AND EXERCISE

描述(改编自申请人摘要)：本提案的目标 是为了研究自主神经系统在生产过程中的作用 反调节激素反应，特别是高血糖素，对温和和 中度低血糖及其对激素的反应 正常和糖尿病犬的适度运动。此信息是 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弱，康复不良。 治疗引起的低血糖和一些易于运动引起的低血糖 低血糖症。这项建议审查了损害的机制 这种低血糖反应和研究人员假设损害了 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表现可能会影响 他们的治疗方法。 提案的第一部分，具体目标1至3，建议确定 胰岛自主神经输入刺激胰高血糖素分泌的作用 在低血糖期间。他们提出了去甲肾上腺素溢出的措施 从清醒的狗的胰腺中提取 静脉导管在中度胰腺神经激活中的应用 低血糖症。他们还建议测试低血糖的假说 相关自主神经衰竭(HAF)通过以下方式损害胰高血糖素的反应 减少非糖尿病犬的这些神经的激活。他们会 然后研究HAAF在新发糖尿病犬或慢性糖尿病犬中的作用 严重高血糖，在长期糖尿病狗假设神经 就会发生功能障碍，从而削弱对 低血糖症。在特定目标1中，既往低血糖对 将检查胰腺神经的激活，并将其确定 如果自主神经输入减少，以及这是否与 非糖尿病犬的胰升糖素反应受损。的影响 将检查高胰岛素血症，而不是低血糖。此外, 将评估糖皮质激素的效果。然后是自主神经 由第一次降糖事件引起的激活将被阻断以评估 随后的损害是否由这种反应调节。到时候他们就会 评估局限性胰岛低血糖是否可能介导 HAAF过程中的胰升糖素反应。在具体目标2中，类似的效果将是 在四氧嘧啶诱导的新糖尿病犬中进行评估，尤其是 还将评估局部胰岛素缺乏的影响。以特定的目标 3，该模型将是一只慢性高血糖的糖尿病犬 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) 将检查通路，并将自主神经激动剂的效果 探索过了。 在具体目标4所述提案的第二部分，他们将 记录下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调节中的作用 运动性胰岛素降低，胰高血糖素分泌增加。 胰腺去甲肾上腺素溢出和甘丙素溢出都将是 在正常和慢性糖尿病犬身上进行评估。此外，当地 胰腺交感神经递质释放将被阻断 为了评估其在胰腺激素反应中的作用 锻炼身体。

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.