Glucose Counterregulation in Long Standing Type 1 Diabetes

长期 1 型糖尿病的血糖反调节

• 批准号: 8239502
• 负责人: Michael R Rickels
• 金额: $ 34.98万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239502
• 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

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. PUBLIC HEALTH RELEVANCE: Impaired glucose counteregulation in long standing type 1 diabetes increases the risk for severe hypoglycemia, an important complication in itself and a significant barrier to the attainment of adequate glycemic control. This proposal will determine whether 2 novel approaches for the treatment of type 1 diabetes, namely islet cell transplantation (specific aim 1) or real-time continuous glucose monitoring (specific aim 2), can restore glucose counterregulation in response to insulin-induced hypoglycemia in patients with long standing disease.

描述（由申请人提供）：低血糖是大多数胰岛素依赖型糖尿病患者（包括 1 型糖尿病患者和晚期 2 型糖尿病患者）实现充分血糖控制的主要障碍。胰岛素绝对缺乏（C 肽阴性）的 1 型糖尿病患者发生严重低血糖事件的风险最大，因为产生胰岛素的胰岛 β 细胞几乎完全破坏，导致邻近 α 细胞的胰高血糖素分泌出现相关缺陷。这些患者依靠交感肾上腺系统作为对抗低血糖的最后防御，但不幸的是，反复发作的低血糖会削弱交感肾上腺的激活，并产生低血糖无意识综合征，与危及生命的低血糖风险增加二十倍相关。如果没有完整的胰岛或交感肾上腺（尤其是肾上腺素）对低血糖的反应，这些患者就无法增加内源性（主要是肝脏）葡萄糖的产生来预防或纠正低血糖。在本申请中，我们建议确定通过两种新的 1 型糖尿病治疗方法（即胰岛细胞移植（具体目标 1）或实时连续血糖监测（RT-CGM；具体目标 2））严格避免低血糖是否可以恢复长期患病患者针对低血糖的内源性葡萄糖生成。在具体目标 1 下，12 名患有长期 1 型糖尿病并发低血糖的受试者在胰岛细胞移植前以及胰岛细​​胞移植后 6 个月和 18 个月时，使用配对的高胰岛素 eu 和低血糖钳以及稳定的葡萄糖同位素输注，评估内源性葡萄糖产生对胰岛素引起的低血糖的反应。根据具体目标 2，12 名未意识到低血糖的类似 1 型糖尿病受试者将在开始 RT-CGM 之前以及开始后 6 个月和 18 个月时对胰岛素引起的低血糖的内源性葡萄糖产生反应进行相同的评估。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 RT-CGM 可能会被中断或无法唤醒熟睡的患者，因此了解这两种方法可以对血糖反调节带来哪些改善至关重要。虽然有些患者可能只适合一种方法或另一种方法，但如果两种方法都被证明可以恢复血糖反调节，则该提案生成的数据将有助于设计细胞疗法与机械疗法对长期血糖反调节反应的未来随机试验，从而提供针对严重低血糖的保护。 公众健康相关性：长期 1 型糖尿病患者的血糖反调节功能受损会增加严重低血糖的风险，低血糖本身就是一种重要的并发症，也是实现充分血糖控制的重大障碍。该提案将确定治疗 1 型糖尿病的 2 种新方法，即胰岛细胞移植（具体目标 1）或实时连续血糖监测（具体目标 2）是否可以恢复长期患病患者的血糖反调节，以应对胰岛素引起的低血糖。