Role of GLP-1 in Congenital Hyperinsulinism

GLP-1 在先天性高胰岛素血症中的作用

• 批准号: 7912924
• 负责人: Diva D. De Leon
• 金额: $ 28.98万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912924
• 关键词: Adult; Affect; Amino Acids; Birth; Blood Glucose; Brain Injuries; C-Peptide; Calcium; Cell physiology; Cessation of life; Child; Continuous Infusion; Cyclic AMP; Diabetes Mellitus; Disease; Drug Kinetics; Exhibits; Failure; Fasting; Fluid overload; Functional disorder; Fundoplication; GLP-I receptor; Gastrostomy; Glucagon; Glucose; Goals; Grant; Half-Life; Heart failure; Hereditary Disease; Hospitalization; Hour; Human; Hyperinsulinism; Hypersensitivity; Hypoglycemia; Infant; Infusion procedures; Insulin; Intestinal Obstruction; Intravenous infusion procedures; Islets of Langerhans; Life; Malabsorption Syndromes; Mediating; Medical; Metabolic; Metabolism; Mus; Mutation; Operative Surgical Procedures; Outcome; Pancreas; Pancreatectomy; Patients; Peptides; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Phenotype; Pilot Projects; Plasma; Play; Population; Postabsorptive Hypoglycemia; Principal Investigator; Proteins; Research; Risk; Rodent; Role; Schedule; Specimen; Testing; Therapeutic; Total Pancreatectomy; Translational Research; Tube; abstracting; bariatric surgery; base; fasting blood glucose level; glucagon-like peptide 1; glucose metabolism; high risk; human subject; improved; insulin secretion; islet; loss of function mutation; mouse model; prevent; primary outcome; programs; research study; response; secondary outcome

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.

项目摘要/摘要 描述 这是对胰高血糖素样肽-1（GLP-1）在先天性的作用的翻译研究 高胰岛素（CHI），这是儿童持续性低血糖的最常见原因。 Chi是遗传 胰腺功能障碍 - 细胞功能的特征是在存在下未能抑制胰岛素分泌 低血糖，如果治疗不足，会导致脑损伤或死亡。功能丧失突变 KATP通道（由两个亚基组成：Kir6.2和Sur-1）是最常见和最严重的 HI的形式（Katphi）。大多数患者对可用的医疗治疗无反应，需要部分 胰腺切除术以控制低血糖，导致住院时间长，威胁生命的高风险 并发症以及糖尿病和吸收不良的风险增加。我们的初步研究表明 GLP-1接收器在缺乏KATP通道（SUR-1 - / - 小鼠的小鼠的胰岛）始终活跃，并且 通过外素（9-39）对GLP-1受体的拮抗作用抑制胰岛素分泌并纠正禁食 这些小鼠的低血糖。这笔赠款的目的是检查脱糖浆（9-39）对葡萄糖的影响 人类受试者具有Katphi的代谢，并检查了抑制（9-39）的机制 缺乏KATP通道的人和啮齿动物胰岛中的胰岛素分泌。我们的总体假设是 Exendin-（9-39）的GLP-1受体将增加空腹血糖水平，防止蛋白质诱导 低血糖和减少葡萄糖的需求，以维持Katphi受试者的葡萄糖症。 抑制胰岛素分泌和增加的谷子水平，这些作用是由变化介导的 蜂窝营地水平。目的1是检查exendin-（9-39）对（a）空腹血糖和（b）的影响 蛋白质诱导的Katphi受试者中的低血糖。受试者将连续注入车辆或 在禁食期间，在蛋白质挑战期间以及遵循正常日常工作时进行评估时（9-39）（9-39） 胡椒对葡萄糖水平的影响。 AIM 2是检查脱发 - （9-39）对葡萄糖的影响 维持先天性高胰岛素主义婴儿对医学无反应的婴儿的尤利克血症的要求 计划进行胰腺切除术的治疗。受试者将连续输注exendin-（9-39） 在输注过程中，将血糖水平> 70 mg/dL维持的葡萄糖要求进行比较 基线要求。 AIM 3是表征从与胰岛隔离的胰岛的代谢燃料反应能力 患有KATP超胰岛素主义的人类受试者，并检查抑制抑制的机制 缺乏KATP通道的胰岛中的胰岛素分泌。胰岛的代谢燃料响应能力隔离 来自患有Katphi儿童和SUR-1-/ - 小鼠的手术标本，以及脱发 - （9-39）对 这些反应将通过渗出和批处理孵育实验来检查。这项研究的结果 将提供基本信息，以评估exendin-（9-39）作为潜在的治疗选择 毁灭性的疾病和理解正常人中与KATP无关的胰岛素分泌的基础。