COUNTERREGULATORY FAILURE AND THE ARCUATE NUCLEUS

描述（申请人摘要）：1型糖尿病的长期并发症 在严格控制血糖水平的患者中， 这种严格控制的一个常见后果是， 低血糖，最终导致低血糖相关的自主神经功能衰竭 和无知低血糖的意识感知降低， 反调节激素分泌的减少使患者处于以下风险中： 深度和长期的低血糖发作，可导致癫痫发作，昏迷，或 死亡该提议描述了一种啮齿动物模型，其中， 低血糖降低交感肾上腺对随后低血糖的反应 情节。一次低血糖发作后观察到的大脑变化包括 弓状核神经肽NPY和POMC的表达减少， 下丘脑和弓形神经元凋亡的证据。本 建议有三个目标，旨在确定机制和功能 大鼠弓状损伤和反调节减少的意义。第一 目的是评估是否低血糖诱导的弓形变化和抑制 反调节反应与低血糖症特异性相关，或 高胰岛素血症是否能在缺乏胰岛素的情况下诱导类似的变化， 低血糖葡萄糖钳夹将用于诱导高胰岛素血症 高胰岛素血症或高胰岛素血症性低血糖，以区分这些 可能性下一个目标是使用下丘脑微量注射 2-脱氧-D-葡萄糖研究弓状核和腹内侧核的 下丘脑内侧基底核，比较和对比这些核团的作用， 行为和内分泌对葡萄糖缺乏刺激的反应。在最后一个目标中， 低血糖引起弓形体改变的潜在功能意义 将被评估。对葡萄糖缺乏刺激的行为和内分泌反应 弓状核在先前的高胰岛素血症/低血糖症后将 作为下丘脑葡萄糖敏感性的指标， 低血糖这些研究的结果将提供以下信息： 低血糖检测的下丘脑机制和关于下丘脑 可能导致低血糖无意识现象的变化 和低血糖相关的自主神经衰竭

DESCRIPTION (Applicant's abstract): Long term complications of type 1 diabetes mellitus are reduced in patients with tightly controlled plasma glucose levels. A frequent consequence of this tight control is repeated episodes of hypoglycemia, ultimately leading to hypoglycemia associated autonomic failure and unawareness. Reduced conscious perception of hypoglycemia coupled with reduced secretion of counterregulatory hormones places patients at risk for deep and prolonged hypoglycemic episodes that can lead to seizures, coma, or death. This proposal describes a rodent model in which a single episode of hypoglycemia reduced sympathoadrenal responses to subsequent hypoglycemic episodes. Brain alterations observed after one bout of hypoglycemia include reduced expression of the neuropeptides NPY and POMC in the arcuate nucleus of the hypothalamus, and evidence of apoptosis in arcuate neurons. The present proposal has three aims directed to determining the mechanism and functional significance of arcuate damage and reduced counterregulation in rats. The first aim is to assess whether hypoglycemia-induced arcuate changes and suppressed counterregulatory responses are related specifically to hypoglycemia, or whether hyperinsulinemia can induce similar changes in the absence of hypoglycemia. A glucose clamp will be used to induce hyperinsulinemic euglycemia or hyperinsulinemic hypoglycemia to distinguish between these possibilities. The next aim is to use hypothalamic microinjections of 2-deoxy-D-glucose to study the arcuate and ventromedial nuclei of the mediobasal hypothalamus, comparing and contrasting the roles of these nuclei in behavioral and endocrine responses to glucoprivic stimulation. In the last aim, the potential functional significance of hypoglycemia-induced arcuate changes will be assessed. Behavioral and endocrine responses to glucoprivic stimulation of the arcuate nucleus after antecedent hyperinsulinemia/hypoglycemia will be measured as an indicator of the glucose sensitivity of the hypothalamus after hypoglycemia. The outcome of these studies will provide information about hypothalamic mechanisms of hypoglycemia detection and about hypothalamic alterations that may contribute to the phenomena of hypoglycemia unawareness and hypoglycemia-associated autonomic failure.