Role of GLP-1 in Congenital Hyperinsulinism

项目摘要/摘要 描述 这是一项关于胰高血糖素样肽-1(GLP-1)在先天性心脏病中作用的翻译研究。 高胰岛素血症(CHI)，儿童持续性低血糖的最常见原因。气是一种基因 胰岛细胞功能紊乱，其特征是在存在的情况下不能抑制胰岛素的分泌 低血糖，如果治疗不当，会导致脑损伤或死亡。细胞功能缺失突变 KATP通道(由Kir6.2和SuR-1两个亚基组成)是最常见和最严重的 HI(KATPHI)的形式。大多数患者对可用的药物治疗没有反应，需要部分 胰腺切除术控制低血糖，导致住院时间延长，危及生命的高风险 并发症，增加患糖尿病和吸收不良的风险。我们的初步研究表明 GLP-1受体在缺乏KATP通道的小鼠(SUR-1-/-小鼠)的胰岛中具有结构性活性，并且 Exendin-(9-39)拮抗GLP-1受体抑制胰岛素分泌和纠正空腹 这些小鼠的低血糖。这项资助的目标是研究exendin-(9-39)对血糖的影响。 KATPHI受试者的代谢及exendin-(9-39)抑制机制的研究 缺乏KATP通道的人和啮齿动物胰岛的胰岛素分泌。我们的总体假设是 GLP-1受体通过exendin-(9-39)会升高空腹血糖水平，防止蛋白质诱导 KATPHI患者的低血糖和降低葡萄糖需要量以维持正常血糖 抑制胰岛素分泌和升高胰高血糖素水平，这些影响是通过改变 细胞内cAMP水平。目的1是研究exendin-(9-39)对(A)空腹血糖和(B)的影响。 KATPHI受试者的蛋白质诱导的低血糖。受试者将接受持续的交通工具或 Exendin-(9-39)在禁食期间、在蛋白质挑战期间以及在遵循正常的日常程序进行评估的同时 多肽对血糖水平的影响。目的2是研究exendin-(9-39)对血糖的影响 对药物无效的先天性高胰岛素血症婴儿维持正常血糖的要求 计划进行胰腺切除治疗的患者。受试者将接受持续输注艾森丁-(9-39) 在输液过程中维持血糖水平70 mg/dL的葡萄糖需要量将与 基线要求。目标3是表征分离的胰岛的代谢燃料反应性。 目的：研究KATP高胰岛素血症患者及exendin-(9-39)抑制KATP高胰岛素血症的机制 缺乏KATP通道的胰岛的胰岛素分泌。离体胰岛的代谢燃料反应性 KATPHI患儿手术标本和SUR-1-/-小鼠标本及exendin-(9-39)的作用 这些反应将通过灌流和批量孵化实验进行检验。这项研究的结果 将为评估exendin-(9-39)作为潜在的治疗方案提供必要的信息 为了解正常人体内KATP非依赖性胰岛素分泌的基础，研究了一种破坏性的疾病。

Project Summary/Abstract Description This is a translational research study of the role of glucagon-like peptide-1 (GLP-1) in congenital hyperinsulinism (CHI), the most frequent cause of persistent hypoglycemia in children. CHI is a genetic disorder of pancreatic ¿-cell function characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if inadequately treated. Loss-of-function mutations in the KATP channel (composed by two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of HI (KATPHI). Most patients are unresponsive to available medical therapy and require partial pancreatectomy to control the hypoglycemia, resulting in prolonged hospitalization, high risk for life-threatening complications, and increased risk for diabetes mellitus and malabsorption. Our preliminary studies demonstrate that the GLP-1 receptor is constitutively active in islets of mice lacking KATP channels (SUR-1-/- mice) and that antagonism of the GLP-1 receptor by exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in these mice. The goal of this grant is to examine the effects of exendin-(9-39) on glucose metabolism of human subjects with KATPHI and to examine the mechanism whereby exendin-(9-39) inhibits insulin secretion in human and rodent islets lacking KATP channels. Our overall hypothesis is that antagonism of the GLP-1 receptor by exendin-(9-39) will increase fasting blood glucose levels, prevent protein-induced hypoglycemia and decrease glucose requirement to maintain euglycemia in subjects with KATPHI as a result of suppressed insulin secretion and increased glucagon levels, and that these effects are mediated by changes in cellular cAMP levels. Aim 1 is to examine the effects of exendin-(9-39) on (a) fasting blood glucose and (b) protein-induced hypoglycemia in subjects with KATPHI. Subjects will receive a continuous infusion of vehicle or exendin-(9-39) during fasting, during a protein challenge, and while following a normal daily routine to evaluate the effects of the peptide on glucose levels. Aim 2 is to examine the effects of exendin-(9-39) on glucose requirements to maintain euglycemia in infants with congenital hyperinsulinism unresponsive to medical therapy who are scheduled for a pancreatectomy. Subjects will receive a continuous infusion of exendin-(9-39) and glucose requirements to maintain blood glucose levels > 70 mg/dL during the infusion will be compared to baseline requirements. Aim 3 is to characterize metabolic fuel responsiveness of pancreatic islets isolated from human subjects with KATP hyperinsulinism and to examine the mechanism whereby exendin-(9-39) suppresses insulin secretion in pancreatic islets lacking KATP channels. The metabolic fuel responsiveness of islets isolated from surgical specimens of children with KATPHI and from SUR-1-/- mice and the effects of exendin-(9-39) on these responses will be examined by perifusion and batch incubation experiments. The results of this research will provide essential information for evaluating exendin-(9-39) as a potential therapeutic option for this devastating disorder and for understanding the basis of KATP-independent insulin secretion in normal humans.