Glucoregulatory Hormone Interactions in Diabetes

低血糖仍然是限制强化胰岛素治疗使用的主要因素，已被证明 预防 1 型糖尿病 (T1DM) 的并发症。该 MERIT 扩展提案继续重点研究 触发葡萄糖反调节并导致低血糖相关疾病发生的机制 自主神经衰竭（HAAF）和低血糖意识。该协议利用独特的啮齿动物 测试特定假设的模型，并在可能的情况下包括对 T1DM 患者的研究。我们会 评估下丘脑腹内侧葡萄糖感应神经元使用的分子机制 (VMM) 激活反监管反应。具体来说，我们测试了低血糖的假设 激活葡萄糖感应中 KATP 通道打开所产生的协调 VMH 信号 神经元导致 GABA 能抑制音下降，从而促进 VMH 葡萄糖抑制的激活 神经元通过燃料感应酶 AMP 激酶。该 VMH 葡萄糖传感模型将作为 旨在改变啮齿动物 VMH 基因表达以评估假定的研究的起点 导致 HAAF 的机制，包括增加 GABA 或 CRF2 受体抑制输入的作用 或 VMH 内 AMP 激酶活性降低。二氮嗪的潜在治疗价值也将是 在血糖反调节受到抑制的强化治疗 T1DM 患者中进行了测试。的影响 胰岛素本身对VMH葡萄糖感应的影响将被确定。我们将检验胰岛素在体内发挥作用的假设 VMH 强效抑制堕胎后状态下的胰高血糖素分泌，并减少胰高血糖素的释放 低血糖期间的胰高血糖素。另外，我们还会继续研究胰岛素对海马功能的影响， 特别是其对记忆功能的有益作用是否会因慢性高血糖而改变。我们还将 检查长期暴露于反复发作的大鼠后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来诊断低血糖。最后我们来评价一下 通过功能磁共振成像和下丘脑血流评估的大脑激活模式如何受到急性发作的影响 与对照组相比，患有严重低血糖的 T1DM 患者的低血糖情况 中链脂肪酸可以减少变化。长期目标是开发新的临床策略 旨在最大限度地降低 T1DM 患者胰岛素引起的低血糖风险。

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.