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：
8447067
负责人：
Michael R Rickels
金额：
$ 33.57万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447067
关键词：
Achievement Adult Alpha Cell Amputation Beta Cell Blindness Blood Glucose C-Peptide Cell secretion Cells Clinical Complication Complications of Diabetes Mellitus Data Defect Development Diabetes Mellitus Diabetic Angiopathies Diabetic Retinopathy Disease Epinephrine Event Failure Food Future Glucagon Glucose Hepatic Hyperglycemia Hypoglycemia Individual Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Isotopes Kidney Diseases Kidney Failure Lead Life Measures Mechanics Neuropathy Non-Insulin-Dependent Diabetes Mellitus Patients Peripheral Recurrence Risk Sleep Symptoms Syndrome System Time Transplant Recipients Transplantation United States counterregulation design diabetic patient experience glucose monitor glucose production glycemic control graft function hypoglycemia unawareness illness length improved insulin secretion islet novel strategies novel therapeutic intervention prevent public health relevance randomized trial response type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most patients with insulin- dependent diabetes, both those with type 1 diabetes and advanced type 2 diabetes. Type 1 diabetic patients with absolute insulin deficiency (C-peptide negative) are at greatest risk for experiencing severe hypoglycemic events because the near total destruction of insulin producing islet beta-cells produces an associated defect in glucagon secretion from neighboring alpha-cells. Such patients then depend on the sympathoadrenal system as a final defense against hypoglycemia, but unfortunately, recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of hypoglycemia unawareness that is associated with a twenty-fold increased risk of life-threatening hypoglycemia. Without intact islet or sympathoadrenal (especially epinephrine) responses to hypoglycemia, these patients cannot increase endogenous (primarily hepatic) glucose production to prevent or correct low blood glucose. In the present application we propose to determine whether strict hypoglycemia avoidance by 2 novel therapeutic approaches for type 1 diabetes, namely islet cell transplantation (specific aim 1) or real-time continuous glucose monitoring (RT-CGM; specific aim 2), can restore endogenous glucose production in response to hypoglycemia in patients with long standing disease. Under specific aim 1, 12 subjects with long standing type 1 diabetes complicated by hypoglycemia unawareness will undergo assessment of the endogenous glucose production response to insulin-induced hypoglycemia using paired hyperinsulinemic eu- and hypoglycemic clamps with stable glucose isotope infusions before and at 6 and 18 months following islet cell transplantation. Under specific aim 2, 12 similar type 1 diabetic subjects with hypoglycemia unawareness will undergo identical assessment of the endogenous glucose production response to insulin-induced hypoglycemia before and at 6 and 18 months following initiation of RT-CGM. Because islet transplant recipients may require some insulin to control hyperglycemia, and because RT-CGM may be interrupted or fail to arouse a sleeping patient, it is critical to understand what improvements in glucose counterregulation may be offered by either approach. While some patients may only be candidates for only one approach or the other, if both approaches are shown to restore glucose counterregulation, the data generated from this proposal will enable the design of future randomized trials of cell vs. mechanical therapy on long-term glucose counterregulatory responses and the protection thus offered against severe hypoglycemia.

描述（由申请人提供）：低血糖是大多数患有胰岛素依赖性糖尿病的患者，包括1型糖尿病和晚期2型糖尿病的患者，是实现足够血糖控制的主要障碍。具有绝对胰岛素缺乏症（C肽阴性）的1型糖尿病患者发生严重的降血糖事件的风险最大，因为胰岛素产生胰岛β细胞的几乎近乎全部破坏会导致邻近α-细胞的胰高血糖素分泌的相关缺陷。这样的患者随后将交感神经系统作为对低血糖的最终防御，但不幸的是，低血糖钝性交感神经肾上腺激活的复发性发作，并产生低血糖综合征，这与二十倍的危及生命的低血糖风险相关。如果没有完整的胰岛或交感肾上腺素（尤其是肾上腺素）对低血糖的反应，这些患者无法增加内源性（主要是肝）葡萄糖的产生，以预防或纠正低血糖。在本应用中，我们建议通过2种新的1型糖尿病治疗方法，即胰岛细胞移植（特定目标1）或实时连续连续葡萄糖监测（RT-CGM;特定目标2），确定2种新型的治疗方法是严格的低血糖方法（特定目标2），我们建议确定严格的低血糖方法（特定的AIM 2），在本应用程序中内源性葡萄糖的产生响应长期疾病患者的低血糖症。在特定的目标1下，有低血糖的12名患有长期型1型糖尿病的受试者不认识将使用成对的高胰岛素EU和低糖症夹在6和18的6和18中评估对胰岛素诱导的低血糖的内源性葡萄糖生产反应。胰岛细胞移植后的几个月。在特定的目标2下，12个类似1型糖尿病患者患有低血糖的人不认识将对内源性葡萄糖产生对胰岛素诱导的低血糖的反应进行相同的评估，此前6和18个月在RT-CGM开始后6和18个月。由于胰岛移植受者可能需要一些胰岛素来控制高血糖，并且由于RT-CGM可能会中断或无法引起熟睡的患者，因此了解两种方法可以提供葡萄糖反调节的改善至关重要。虽然某些患者只能是一种方法或另一种方法，但如果证明两种方法可以恢复葡萄糖反调节，则该提案产生的数据将使细胞与机械治疗的未来随机试验在长期葡萄糖上进行设计。反对反应和因此针对严重低血糖症提供的保护。