Glucose Counterregulation in Long Standing Type 1 Diabetes

描述(申请人提供)：低血糖是大多数胰岛素依赖型糖尿病患者实现适当血糖控制的主要障碍，包括1型糖尿病患者和晚期2型糖尿病患者。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细胞几乎完全被破坏，导致邻近α细胞分泌的胰高血糖素出现相关缺陷。这些患者随后依赖交感肾上腺系统作为对抗低血糖的最终防御，但不幸的是，反复发作的低血糖会削弱交感肾上腺的激活，并产生一种低血糖综合征，这种综合征与威胁生命的低血糖风险增加20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，我们建议确定通过两种治疗1型糖尿病的新方法，即胰岛细胞移植(特异性目标1)或实时连续血糖监测(RT-CGM；特异性目标2)来严格避免低血糖是否可以恢复长期疾病患者的内源性葡萄糖产生以应对低血糖。在特定目标1下，12名长期存在的1型糖尿病合并低血糖的患者将在胰岛细胞移植前、移植后6个月和18个月接受内源性葡萄糖产生对胰岛素诱导的低血糖的反应的评估，使用配对的高胰岛素欧洲和低血糖钳结合稳定的葡萄糖同位素输注。在特定目标2下，12名不知道低血糖的相似的1型糖尿病患者将在RT-CGM开始前以及开始后6个月和18个月接受相同的内源性葡萄糖产生反应的评估。由于胰岛移植受者可能需要一些胰岛素来控制高血糖，而且RT-CGM可能被中断或无法唤醒睡眠中的患者，因此了解这两种方法在血糖反调节方面的改善是至关重要的。虽然一些患者可能只适合其中一种方法，但如果两种方法都被证明可以恢复血糖反调节，从这项建议产生的数据将使未来设计细胞疗法与机械疗法的长期葡萄糖反调节反应的随机试验，以及由此提供的针对严重低血糖的保护。 公共卫生相关性：长期存在的1型糖尿病患者的葡萄糖反调节受损增加了严重低血糖的风险，严重低血糖本身就是一个重要的并发症，也是达到适当的血糖控制的一个重要障碍。这项建议将确定两种治疗1型糖尿病的新方法，即胰岛细胞移植(特定目标1)或实时连续血糖监测(特定目标2)是否能够恢复对长期疾病患者胰岛素诱导的低血糖的血糖抵消调节。

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.