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

Exendin-(9-39) 对高胰岛素血症受试者葡萄糖代谢的影响

• 批准号: 7290256
• 负责人: Diva D. De Leon
• 金额: $ 8.25万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290256
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Address; Animal Model; Blood Glucose; Brain Injuries; Cell physiology; Cells; Cessation of life; Characteristics; Child; Condition; Development; Diabetes Mellitus; Disease; Dose; Enrollment; Enzymes; Failure; Fasting; Functional disorder; GLP-I receptor; Genes; Glucagon; Glucokinase; Glucose; Glutamate Dehydrogenase; Goals; Hereditary Disease; Human; Hyperinsulinism; Hypoglycemia; Infusion procedures; Insulin; Intestines; K-Series Research Career Programs; L Cells; Label; Length of Stay; Life; Malabsorption Syndromes; Medical; Membrane Potentials; Metabolic; Mitochondria; Mus; Mutation; Outcome; Pancreas; Pancreatectomy; Pathogenesis; Patients; Peptides; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Pilot Projects; Plasma; Play; Postabsorptive Hypoglycemia; Potassium Channel; Risk; Role; Testing; Therapeutic; Total Pancreatectomy; base; blood glucose regulation; exenatide; glucagon-like peptide 1; glucose metabolism; impaired glucose tolerance; incretin hormone; insulin secretion; loss of function mutation; mouse model; sulfonylurea receptor

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.

描述（由申请人提供）： 先天性高胰岛素（CHI）是一种胰腺的遗传疾病（-CELL功能，其特征是在存在低血糖的情况下未能抑制胰岛素分泌，如果接受不足的治疗，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。五个基因与SULEA相关。纠正钾通道（KIR6.2），葡萄糖酶（GCK），谷氨酸脱氢酶（GLUD-1）和线粒体酶短链3-羟基乙酰基-COA-COA脱水酶脱水酶（HADHSC）的损失（HADHSC）均由kat-1 compun compunt and-kat surnitions and-kat。 HI的严重形式（Katphi）对可用的医疗疗法无反应，需要部分胰腺切除术才能控制低血糖，导致住院时间长，威胁生命的并发症的高风险，并增加了糖尿病的风险。除细胞内ATP浓度外，它在葡萄糖刺激的胰岛素分泌中的作用（ - 最近的研究表明，KATP通道可能在葡萄糖传感和葡萄糖样肽-1（GLP-1（GLP-1））中发挥作用。在此应用中，我们提出的胰岛素分泌失调。 exendin-（9-39）在Katphi的动物模型中提高了血浆葡萄糖水平。 KATP HI由于胰岛素分泌和葡萄糖水平的增加而是一项开放式标签，其目标是在以下目的中测试10个受试者。在三种不同的剂量下，在患有Katphi的受试者的空腹血糖水平上进行了100、300和500 pmol/kg/min。 Exendin-（9-39）或车辆。 迄今为止，由于KATP通道中的突变引起的先天性超胰岛素主义受试者尚无有效的医疗疗法，因此，此处提出的研究对于进一步了解该疾病的病理生理学非常重要，并评估GLP-1受体拮抗剂在这种疾病治疗中的潜在治疗应用。