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.

项目总结/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转化研究。 高胰岛素血症（CHI）是儿童持续性低血糖的最常见原因。CHI是一种基因 胰腺细胞功能紊乱，特征是在存在胰岛素的情况下不能抑制胰岛素分泌 低血糖，如果治疗不当，会导致脑损伤或死亡。基因中的功能丧失突变 KATP通道（由Kir6.2和SUR-1两个亚基组成）负责最常见和最严重的 HI（KATPHI）。大多数患者对现有的药物治疗无反应，需要部分 胰腺切除术控制低血糖，导致住院时间延长，危及生命的风险高 并发症，并增加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）的胰岛中具有组成性活性， exendin-（9-39）对GLP-1受体的拮抗作用抑制胰岛素分泌并纠正空腹 低血糖的小鼠。这项资助的目的是研究exendin-（9-39）对葡萄糖的影响 本发明的目的是用KATPHI检测人类受试者的代谢，并检查毒蜥外泌肽-（9-39）抑制KATPHI的机制。 缺乏KATP通道的人类和啮齿类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）将增加空腹血糖水平，阻止蛋白诱导的 低血糖和降低葡萄糖需求以维持KATPHI受试者的正常血糖， 抑制胰岛素分泌和增加胰高血糖素水平，这些作用是通过 细胞cAMP水平。目的1是检测exendin-（9-39）对（a）空腹血糖和（B） KATPHI受试者中蛋白质诱导的低血糖。受试者将接受连续输注溶媒或 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生活时，以评估 肽对葡萄糖水平的影响。目的二是研究exendin-（9-39）对血糖的影响 对药物治疗无反应的先天性高胰岛素血症婴儿维持正常血糖的要求 接受胰腺切除术的病人受试者将接受exendin-（9-39）连续输注 并且将在输注期间维持血糖水平> 70 mg/dL的葡萄糖需求与 基线要求。目的3是表征分离自人胰腺的胰岛的代谢燃料反应性。 本发明的目的在于检测具有KATP高胰岛素血症的人类受试者，并检测毒蜥外泌肽-（9-39）抑制胰岛素分泌的机制， 缺乏KATP通道的胰岛的胰岛素分泌。分离的胰岛的代谢燃料反应性 来自KATPHI患儿和SUR-1-/-小鼠的手术标本，以及毒蜥外泌肽-（9-39）对 将通过灌流和批量孵育实验来检查这些反应。这项研究成果 将为评估exendin-（9-39）作为一种潜在的治疗选择提供必要的信息。 破坏性疾病和了解KATP非依赖性胰岛素分泌的基础在正常人。