Glucose counterregulation in long standing type 1 diabetes

长期 1 型糖尿病的血糖反调节

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要低血糖对1型糖尿病和高级2型糖尿病以及需要新的策略来恢复针对的生理防御机制严重降血糖发作的发展。该应用程序的总体目的是增强了解导致葡萄糖反调节和低血糖的机制长期有1型糖尿病和低血糖的患者的症状识别通过对有问题低血糖的改善的新型细胞和技术方法的研究。该应用基于我们最近的研究，表明肝内胰岛细胞移植可以恢复胰岛细胞和交感肾脏对低血糖的反应，并使缺陷葡萄糖正常化反调节。这种作用是否取决于交感神经或激素（肾上腺素）输入移植胰岛是未知的，将在本提案中进行调查以了解其重要性为了保护低血糖，并告知努力从干细胞中得出胰岛进行移植肝脏。此外，我们已经表明实施实时连续葡萄糖监测可以显着改善了内源性葡萄糖对胰岛素诱导的低血糖的反应，尽管直到干预后18个月才观察到葡萄糖反调节的这种改善。无论残留的夜间低血糖可能会延迟葡萄糖反调节的恢复目前的提案实施通过连续的葡萄糖监测，避免过夜低血糖避免和自动暂停胰岛素输送。具体而言，我们将检查1）是否恢复葡萄糖肝内胰岛移植提供的反调节取决于胰岛的肾上腺素能输入，在没有胰岛移植的情况下2）是否更严格避免了低血糖。胰岛素输送的自动悬浮液可以恢复长期持续的患者的葡萄糖反调节疾病，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识别缺乏生理反应的患者可以防御低血糖的发展。