Glucose Counterregulation in Long Standing Type 1 Diabetes

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型糖尿病和晚期2型糖尿病患者）实现充分血糖控制的主要障碍。具有绝对胰岛素缺乏（C肽阴性）的1型糖尿病患者处于经历严重低血糖事件的最大风险，因为产生胰岛素的胰岛β细胞的几乎完全破坏产生来自相邻α细胞的胰高血糖素分泌的相关缺陷。这样的患者依赖于交感肾上腺系统作为对低血糖的最终防御，但不幸的是，低血糖的反复发作会减弱交感肾上腺激活，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。在本申请中，我们提出确定通过用于1型糖尿病的2种新治疗方法，即胰岛细胞移植（具体目标1）或实时连续葡萄糖监测（RT-CGM;具体目标2），严格避免低血糖是否可以恢复响应于长期疾病患者中的低血糖的内源性葡萄糖产生。在具体目标1下，12名患有长期1型糖尿病并发低血糖无意识的受试者将在胰岛细胞移植前和移植后6个月和18个月时使用成对的高胰岛素血症性血糖钳夹和低血糖钳夹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诱导的低血糖的反应。根据具体目标2，12例相似的1型糖尿病低血糖无意识受试者将在开始RT-CGM之前以及开始RT-CGM后6个月和18个月时接受相同的内源性葡萄糖生成对胰岛素诱导低血糖反应的评估。因为胰岛移植受者可能需要一些胰岛素来控制高血糖，并且因为RT-CGM可能被中断或无法唤醒睡眠患者，所以了解任何一种方法都可以提供哪些葡萄糖反调节的改善是至关重要的。虽然有些患者可能只适合一种方法或另一种方法，但如果两种方法都能恢复葡萄糖反调节，则该提案产生的数据将能够设计未来的细胞与机械治疗对长期葡萄糖反调节反应的随机试验，并因此提供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，这本身就是一种重要的并发症，也是实现充分血糖控制的重要障碍。该提案将确定2种治疗1型糖尿病的新方法，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对胰岛素诱导的低血糖的葡萄糖反调节。

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.