COUNTERREGULATORY FAILURE AND THE ARCUATE NUCLEUS

描述(申请人摘要)：1型糖尿病的长期并发症 血糖水平得到严格控制的患者患糖尿病的几率降低。 这种严格控制的一个常见后果是反复发生 低血糖，最终导致低血糖相关的自主神经衰竭 和不知不觉。减少对低血糖的有意识的感知，并伴随 反调节荷尔蒙分泌减少会使患者面临 深度和长期的低血糖发作可导致癫痫发作、昏迷或 死亡。这项提案描述了一种啮齿动物模型，在该模型中， 低血糖降低交感肾上腺对后续低血糖的反应 剧集。在一次低血糖后观察到的脑变化包括 神经肽Y和POMC在大鼠弓状核的表达减少 下丘脑，以及弓状神经元细胞凋亡的证据。现在 提案有三个目标，旨在确定机制和功能 大鼠弓状核损伤和反调节减少的意义。第一 目的是评估低血糖引起的弓状核改变和抑制 反调节反应特别与低血糖有关，或者 高胰岛素血症是否会引起类似的变化 低血糖症。将使用葡萄糖钳夹来诱导高胰岛素血症 正常血糖或高胰岛素血症低血糖的区别 可能性。下一个目标是使用下丘脑微量注射 2-脱氧-D-葡萄糖对大鼠弓状核和腹内侧核的研究 下丘脑内侧基底核，比较和对比这些核团在脑内的作用。 对葡萄糖刺激的行为和内分泌反应。在最后一个目标中， 低血糖引起弓状核改变的潜在功能意义 将会被评估。对葡萄糖刺激的行为和内分泌反应 高胰岛素血症/低血糖后弓状核的 测量作为下丘脑葡萄糖敏感性的一个指示器 低血糖症。这些研究的结果将提供关于 下丘脑低血糖的检测机制及对下丘脑的影响 可能导致低血糖无意识现象的改变 以及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.