Effect of exendin-(9-39) on glucose metabolism in subjects with hyperinsulinism

描述（由申请人提供）： 先天性高胰岛素血症（CHI）是一种胰腺β-细胞功能的遗传性疾病，其特征是在低血糖的情况下不能抑制胰岛素分泌，如果治疗不当，会导致脑损伤或死亡。在儿童中，CHI是持续性低血糖的最常见原因。五个基因的突变与CHI相关：磺酰脲受体（SUR-1）、内向整流钾通道（Kir6.2）、葡萄糖激酶（GCK）、谷氨酸脱氢酶（GLUD-1）和线粒体酶短链3-羟酰辅酶A脱氢酶（HADHSC）。KATP通道（由两个亚基组成：Kir6.2和SUR-1）中的功能丧失突变导致最常见和最严重的HI（KATPHI）。大多数患者对可用的药物治疗无反应，需要部分胰腺切除术来控制低血糖，导致住院时间延长，危及生命的并发症风险高，糖尿病和吸收不良风险增加。KATP敏感性通道通过感知细胞内ATP浓度的变化将β细胞的代谢状态与膜电位偶联。最近的研究表明，KATP通道除了在葡萄糖刺激的β-细胞胰岛素分泌中发挥作用外，还可能在肠L-细胞的葡萄糖敏感和胰高血糖素样肽-1（GLP-1）分泌中发挥作用。作为职业发展奖的一部分，我们正在验证KATPHI中GLP-1分泌异常在胰岛素分泌失调中发挥作用的假设。在本申请中，我们拟研究GLP-1受体（GLP-1 r）拮抗剂exendin-（9-39）对KATPHI受试者葡萄糖代谢的影响。Exendin-（9-39）作为GLP-1 r的特异性和竞争性拮抗剂，增加血浆胰高血糖素水平并抑制胰岛素。在正常受试者中，exendin-（9-39）升高空腹血糖水平。在KATPHI的动物模型中，我们已经表明exendin-（9-39）显著改善空腹低血糖。我们的总体假设是，由于胰岛素分泌受抑制和胰高血糖素水平升高，毒蜥外泌肽-（9-39）对GLP-1受体的拮抗作用将增加患有KATP HI的受试者的空腹血糖水平，并降低葡萄糖需求以维持正常血糖。这是一项开放标签初步研究，目标是入组10例KATPHI受试者。将在以下目的中检验该假设：1）评估升高患有KATP HI的受试者的空腹血糖水平所需的exendin-（9-39）的剂量。我们将检查以三种不同剂量：100、300和500 pmol/kg/min静脉内施用的毒蜥外泌肽-（9-39）对患有KATPHI的受试者的空腹血糖水平的影响。2)在KATP HI受试者中检查GLP-1受体拮抗剂对葡萄糖需求的影响，以维持正常血糖。我们将评估在存在毒蜥外泌肽-（9-39）或媒介物的情况下，KATPHI受试者禁食过夜后维持正常血糖的葡萄糖需求。如果我们的假设被证明是正确的，那么exendin-（9-39）对GLP-1 r的拮抗作用将是这些受试者的潜在治疗选择。 迄今为止，由于KATP通道突变而导致的先天性高胰岛素血症受试者尚无有效的药物治疗，因此，本文拟定的研究对于进一步了解该疾病的病理生理学和评价GLP-1受体拮抗剂在治疗该疾病中的潜在治疗应用非常重要。

DESCRIPTION (provided by applicant): Congenital hyperinsulinism (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. In children, CHI is the most common cause of persistent hypoglycemia. Mutations in five genes have been associated with CHI: the sulfonylurea receptor (SUR-1), an inward rectifying potassium channel (Kir6.2), glucokinase (GCK), glutamate dehydrogenase (GLUD-1), and the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). 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 hospital stays, high risk for life-threatening complications, and increased risk for diabetes mellitus and malabsorption. The KATP-sensitive channels couple the metabolic state of the (-cell to membrane potential by sensing changes in intracellular ATP concentration. In addition to its role in glucose-stimulated insulin secretion in (-cells, recent studies suggest that the KATP channels may play a role in glucose sensing and secretion of glucagon-like peptide-1 (GLP-1) by intestinal L-cells. As part of a career development award we are testing the hypothesis that abnormal GLP-1 secretion in KATPHI plays a role in the dysregulated insulin secretion. In this application we propose to study the effect of the GLP-1 receptor (GLP-1r) antagonist, exendin-(9-39), on glucose metabolism in subjects with KATPHI. Exendin-(9-39), acts as a specific and competitive antagonist of the GLP-1r increasing plasma glucagon levels and suppressing insulin. In normal subjects, exendin-(9-39) raises fasting plasma glucose levels. In an animal model of KATPHI we have shown that exendin-(9-39) significantly ameliorates the fasting hypoglycemia. Our overall hypothesis is that antagonism of the GLP-1 receptor by exendin-(9-39) will increase fasting blood glucose levels and decrease glucose requirement to maintain euglycemia in subjects with KATP HI as a result of suppressed insulin secretion and increased glucagon levels. This is an open label pilot study with a goal to enroll 10 subjects with KATPHI. The hypothesis will be tested in the following aims: 1) To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with KATP HI. We will examine the effect of exendin-(9-39) administered intravenously at three different doses: 100, 300, and 500 pmol/kg/min on fasting blood glucose levels in subjects with KATPHI. 2) To examine the effect of GLP-1 receptor antagonism on glucose requirements to maintain euglycemia in subjects with KATP HI. We will assess glucose requirements to maintain euglycemia after an overnight fast in subjects with KATPHI in the presence of exendin-(9-39) or vehicle. If our hypothesis proves true, antagonism of the GLP-1r by exendin-(9-39) will be a potential therapeutic option for these subjects. To date, there is no effective medical therapy for subjects with congenital hyperinsulinism due to mutations in the KATP channel, therefore, the studies proposed here are important to further our understanding of the pathophysiology of this disorder and to evaluate the potential therapeutic applications of GLP-1 receptor antagonists in the treatment of this condition.