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)是一种遗传性的胰腺细胞功能障碍，其特征是在低血糖的情况下无法抑制胰岛素的分泌，如果治疗不当会导致脑损伤或死亡。在儿童中，CHI是持续低血糖的最常见原因。与CHI相关的基因有5个：磺脲类受体(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)和线粒体短链3-羟基酰辅酶A脱氢酶(HADHSC)。KATP通道(由两个亚基：Kir6.2和SuR-1组成)功能丧失突变是最常见和最严重的HI(KATPHI)的原因。大多数患者对现有的药物治疗没有反应，需要胰腺部分切除术来控制低血糖，导致住院时间延长，危及生命的并发症的高风险，以及糖尿病和吸收不良的风险增加。KATP敏感通道通过感知细胞内ATP浓度的变化，将(-细胞)的代谢状态与膜电位联系起来。最近的研究表明，KATP通道除了在葡萄糖刺激的胰岛素分泌中发挥作用外，还可能在肠道L细胞的葡萄糖感应和分泌胰升糖素样肽-1(GLP-1)中发挥作用。作为职业发展奖的一部分，我们正在测试一种假设，即KATPHI中异常的GLP-1分泌在胰岛素分泌失调中发挥了作用。在这项应用中，我们建议研究GLP-1受体(GLP-1R)拮抗剂exendin-(9-39)对KATPHI患者糖代谢的影响。Exendin-(9-39)，作为GLP-1R的特异性和竞争性拮抗剂，升高血浆胰高血糖素水平和抑制胰岛素。在正常受试者中，exendin-(9-39)可提高空腹血糖水平。在KATPHI的动物模型中，我们已经证明Exendin-(9-39)可以显着改善空腹低血糖。我们的总体假设是，Exendin-(9-39)对GLP-1受体的拮抗作用将提高KATPHI患者的空腹血糖水平，并降低维持正常血糖所需的葡萄糖需求，这是由于胰岛素分泌受到抑制和胰高血糖素水平升高所致。这是一项开放标签的先导性研究，目标是招募10名KATPHI受试者。这一假设将在以下目标中进行检验：1)评估KATPHI患者提高空腹血糖水平所需的exendin-(9-39)剂量。我们将检查静脉注射三种不同剂量的exendin-(9-39)：100、300和500pmol/kg/min对KATPHI患者空腹血糖水平的影响。2)研究GLP-1受体拮抗剂对KATPHI患者维持正常血糖所需血糖的影响。我们将评估在服用exendin-(9-39)或赋形剂的情况下，KATPHI受试者在隔夜禁食后维持正常血糖所需的葡萄糖需求。如果我们的假设被证明是正确的，Exendin-(9-39)拮抗GLP-1R将是这些受试者的一个潜在的治疗选择。 到目前为止，由于KATP通道突变而导致的先天性高胰岛素血症尚无有效的药物治疗方法，因此，本文提出的研究对于加深我们对这种疾病的病理生理机制的理解和评估GLP-1受体拮抗剂在治疗这种疾病中的潜在治疗应用具有重要意义。

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.