Glucose Counterregulation in Long Standing Type 1 Diabetes

描述（由申请人提供）：对于大多数胰岛素依赖型糖尿病患者，包括1型糖尿病和晚期2型糖尿病患者，低血糖是实现充分血糖控制的主要障碍。绝对胰岛素缺乏（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细胞几乎被完全破坏，导致邻近α细胞分泌胰高血糖素的缺陷。这些患者依赖交感肾上腺系统作为对抗低血糖的最后防线，但不幸的是，低血糖的反复发作会减弱交感肾上腺的激活，并产生低血糖无意识综合征，这与危及生命的低血糖风险增加20倍有关。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，这些患者不能增加内源性（主要是肝脏）葡萄糖的产生来预防或纠正低血糖。在目前的应用中，我们提出通过两种新的1型糖尿病治疗方法，即胰岛细胞移植（特异性目的1）或实时连续血糖监测（RT-CGM；特异性目的2）来确定严格避免低血糖是否可以恢复长期患病患者对低血糖的内源性葡萄糖产生。在特定的目的下，12名长期患有1型糖尿病并低血糖意识不清的受试者将在胰岛细胞移植前、移植后6个月和18个月使用稳定葡萄糖同位素输注的高胰岛素血症eu-和低血糖钳对胰岛素诱导的低血糖进行内源性葡萄糖生成反应的评估。在特定的目标2中，12名相似的1型糖尿病患者在开始RT-CGM前、6个月和18个月接受相同的内源性葡萄糖生成对胰岛素诱导的低血糖反应的评估。由于胰岛移植受者可能需要一些胰岛素来控制高血糖，并且由于RT-CGM可能会中断或无法唤醒睡眠中的患者，因此了解这两种方法在葡萄糖反调节方面的改善是至关重要的。虽然有些患者可能只适合一种或另一种方法，但如果两种方法都能恢复葡萄糖反调节，那么本提案产生的数据将有助于设计未来的随机试验，比较细胞治疗和机械治疗对长期葡萄糖反调节反应的影响，并由此提供对严重低血糖的保护。

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.