Glucose counterregulation in long standing type 1 diabetes

长期 1 型糖尿病的血糖反调节

• 批准号: 9303341
• 负责人: Michael R Rickels
• 金额: $ 40.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303341
• 关键词: Achievement; Adrenergic Agents; Adrenergic Antagonists; Adrenergic alpha-Antagonists; Adult; Alpha Cell; Attenuated; BCL9 gene; Blood Glucose; C-Peptide; Cell Transplantation; Clinical; Closure by clamp; Data; Defense Mechanisms; Development; Devices; Disease; Double-Blind Method; Epinephrine; Failure; Generations; Glucagon; Glucose; Gold; Hepatic; Hormonal; Hyperinsulinism; Hypoglycemia; Impairment; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Islet Cell; Islets of Langerhans Transplantation; Lead; Life Experience; Liver; Measures; Mediating; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Patients; Phentolamine; Physiological; Placebos; Propranolol; Pump; Randomized; Records; Recovery; Recurrence; Residual state; Risk; Severities; Standardization; Suspensions; Symptoms; Syndrome; Therapeutic; Time; Transplantation; Validation; base; counterregulation; diabetic patient; experience; falls; glucose monitor; glucose production; glucose sensor; glycemic control; hormone regulation; hypoglycemia unawareness; improved; indexing; insulin secretion; intrahepatic; islet; islet stem cells; mortality; novel; polypeptide C; post intervention; relating to nervous system; response; sensor; standard measure; treatment strategy; type I diabetic

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.

项目摘要 低血糖显著影响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。该应用程序的总体目标是增强 了解有助于恢复葡萄糖反调节和低血糖的机制 长期存在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来改善问题性低血糖。 这项应用建立在我们最近的研究基础上，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，并使缺陷葡萄糖正常化 反调节这种效应是否依赖于交感神经或激素（肾上腺素）输入， 移植的胰岛是未知的，将在本提案中进行调查，以了解其重要性 保护免受低血糖，并为从干细胞中提取胰岛用于体外移植的努力提供信息。 肝脏此外，我们已经表明，实施实时连续葡萄糖监测可以 显著改善对胰岛素诱导的低血糖的内源性葡萄糖产生反应，尽管 直到干预后18个月才观察到葡萄糖反调节的这种改善。是否 残留的夜间低血糖可能会延迟葡萄糖反调节的恢复， 本提案通过使用连续葡萄糖监测来实现夜间低血糖避免 和自动暂停胰岛素输注。具体来说，我们将研究1）葡萄糖的恢复是否 肝内胰岛移植提供的反调节依赖于对胰岛的肾上腺素能输入， 以及在没有胰岛移植的情况下，2）是否更严格地避免低血糖， 自动暂停胰岛素输注可以恢复长期站立的患者的葡萄糖反调节 最后3）低血糖严重程度和血糖不稳定性的临床指标是否准确识别 缺乏防御低血糖发展所需的生理反应的患者。