Glucose counterregulation in long standing type 1 diabetes

项目总结 低血糖在很大程度上导致1型糖尿病患者的发病率和死亡率 晚期2型糖尿病，需要新的策略来恢复生理防御机制 严重低血糖发作的发展。此应用程序的总体目标是增强 对葡萄糖逆调节和低血糖恢复机制的认识 长期存在的1型糖尿病和低血糖无意识患者的症状识别 研究新的细胞和技术方法以改善有问题的低血糖。 这一应用建立在我们最近的研究基础上，该研究表明肝内胰岛细胞移植可以 恢复胰岛细胞和交感肾上腺对低血糖的反应并使有缺陷的葡萄糖正常化 反监管。这种作用是否依赖于交感神经或荷尔蒙(肾上腺素)对 移植的胰岛是未知的，将在目前的提案中进行调查，以了解其重要性。 以防止低血糖，并为从干细胞中获取胰岛以移植到国外的努力提供信息 肝脏。此外，我们还表明，实施实时连续血糖监测可以 显著改善内源性葡萄糖产生对胰岛素诱导的低血糖的反应，尽管 直到干预后18个月，才观察到血糖反调节的改善。是否 夜间残余低血糖可能会延缓血糖恢复，将在 目前建议使用连续血糖监测来避免过夜低血糖 和自动暂停胰岛素输送。具体地说，我们将检查1)葡萄糖的恢复 肝内胰岛移植提供的逆调节依赖于对胰岛的肾上腺素能输入， 在没有胰岛移植的情况下2)是否更严格地避免低血糖 自动停用胰岛素可恢复长期低血糖患者的血糖反调节 疾病，以及最后3)低血糖严重程度和血糖不稳定的临床指标是否准确地识别 缺乏生理反应的患者需要预防低血糖的发生。

PROJECT SUMMARY Hypoglycemia contributes substantially to the morbidity and mortality of patients with type 1 diabetes and advanced type 2 diabetes, and new strategies are needed to restore physiologic defense mechanisms against the development of severe hypoglycemic episodes. The overall aim of this application is to enhance understanding of the mechanisms contributing to the recovery of glucose counterregulation and hypoglycemia symptom recognition in patients with long standing type 1 diabetes and hypoglycemia unawareness through the investigation of novel cellular and technologic approaches to the amelioration of problematic hypoglycemia. This application builds on our recent studies demonstrating that intrahepatic islet cell transplantation can restore both islet cell and sympathoadrenal responses to hypoglycemia and normalize defective glucose counterregulation. Whether this effect is dependent on sympathetic neural or hormonal (epinephrine) input to the transplant islets is unknown, and will be investigated in the present proposal to understand its importance to protection from hypoglycemia, and inform efforts to derive islets from stem cells for transplantation outside of the liver. In addition, we have shown that implementation of real-time continuous glucose monitoring can significantly improve the endogenous glucose production response to insulin-induced hypoglycemia, although this improvement in glucose counterregulation was not observed until 18 months post-intervention. Whether residual nocturnal hypoglycemia may delay recovery in glucose counterregulation will be examined in the present proposal implementing overnight hypoglycemia avoidance with use of continuous glucose monitoring and automated suspension of insulin delivery. Specifically, we will examine 1) whether the recovery of glucose counterregulation afforded by intrahepatic islet transplantation is dependent on adrenergic input to the islets, and in the absence of an islet transplant 2) whether more stringent avoidance of hypoglycemia afforded by automated suspension of insulin delivery can restore glucose counterregulation in patients with long standing disease, and finally 3) whether clinical metrics of hypoglycemia severity and glycemic lability accurately identify patients with absent physiologic responses required to defend against the development of low blood glucose.