Glucoregulatory Hormone Interactions in Diabetes

低血糖仍然是限制使用强化胰岛素疗法的主要因素，这种疗法已被证明可以 预防1型糖尿病(T1 DM)的并发症。这项优点延期建议继续进行重点研究 引发血糖逆调节并导致低血糖发生的机制 自主神经衰竭(HAF)和低血糖意识不清。协议利用了独特的啮齿动物 测试特定假设的模型，并在可能的情况下包括对T1 DM患者的研究。我们会 评价下丘脑腹内侧葡萄糖敏感神经元的分子机制 (VMM)以激活反监管反应。具体地说，我们测试了低血糖的假设 激活糖感应中KATP通道开放所产生的协调VMH信号 引起GABA能抑制张力下降的神经元促进糖抑制的VMH的激活 神经元受燃料感受酶--AMP-激酶的影响。这种VMH血糖传感模型将作为 旨在改变啮齿动物VMH基因表达以评估推测的研究的起点 HAAF的机制，包括增加GABA或CRF2受体抑制输入的作用 或VMH内AMP-K活性降低。二氮嗪的潜在治疗价值也将是 在接受强化治疗的T1 DM患者中进行了测试，发现受抑的血糖水平存在反向调节。的影响 胰岛素本身对VMH葡萄糖传感的影响将被确定。我们将检验胰岛素在体内起作用的假设 VMH强的抑制流产后状态的胰高血糖素的分泌，并减少释放 低血糖时的高血糖素。此外，我们还将继续研究胰岛素对海马体功能的影响， 特别是它对记忆功能的有益影响是否会因慢性高血糖而改变。我们还将 检测长期暴露于反复暴露后大鼠认知能力改善的机制 使用磁共振波谱以及基因组和蛋白质组分析进行低血糖。最后，我们将评估 急性呼吸窘迫综合征对脑激活模式和下丘脑血流量的影响 与对照组相比，有严重低血糖意识的T1 DM患者发生低血糖，如果是这样 中链脂肪酸可以减少这种变化。长期目标是开发新的临床策略。 目的是将T1 DM患者胰岛素诱导低血糖的风险降至最低。

Hypoglycemia remains the major factor limiting the use of intensified insulin therapy that has been shown to prevent complications in type 1 diabetes (T1DM). This MERIT extension proposal continues studies focused on the mechanisms that trigger glucose counterregulation and lead to the development of hypoglycemiaassociated autonomic failure (HAAF) and hypoglycemia unawareness. The protocols utilize unique rodent models to test specific hypotheses, and where possible include studies in patients with T1DM. We will evaluate the molecular mechanisms used by glucose-sensing neurons in the ventromedial hypothalamus (VMM) to activate counterregulatory responses. Specifically, we test the hypothesis that hypoglycemia activates a coordinated VMH signal that results from the opening of KATP channels in glucose-sensing neurons causing a drop in GABAergic inhibitory tone that promotes the activation of VMH glucose-inhibited neurons by the fuel sensing enzyme, AMP-kinase. This model of VMH glucose sensing will serve as a starting point for studies directed at altering VMH gene expression in rodents to evaluate putative mechanisms responsible for HAAF, including the role of increased GABA or CRF2 receptor inhibitory input or decreased AMP-kinase activity within the VMH. The potential therapeutic value of diazoxide will also be tested in intensively treated T1DM patients with suppressed glucose counterregulation. The influence of insulin per se on VMH glucose sensing will be determined. We will test the hypothesis that insulin acts within the VMH to tonically suppress glucagon secretion in the postaborptive state and to diminish the release of glucagon during hypoglycemia. In addition, we will continue study insulin's effect on hippocampus function, specifically whether its beneficial effect on memory function is altered by chronic hyperglycemia. We will also examine the mechanisms for improved cognitive performance in rats after long-term exposure to recurrent hypoglycemia using MR spectroscopy as well as genomic and proteomic analyses. Finally, we will evaluate how brain activation patterns assessed by fMRI and hypothalamic blood flow are affected by acute hypoglycemia in T1DM patients with severe hypoglycemia unawareness as compared to controls and if such changes are reduced by medium chain fatty acids. The long-term goal is to develop novel clinical strategies aimed at minimizing the risk of insulin-induced hypoglycemia in patients with T1DM.