Role of GLP-1 in disorders of carbohydrate metabolism in children

GLP-1 在儿童碳水化合物代谢紊乱中的作用

• 批准号: 7026155
• 负责人: Diva D. De Leon
• 金额: $ 13.3万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026155
• 关键词: blood chemistry; carbohydrate metabolism; children; clinical research; congenital disorders; gene mutation; genetically modified animals; glucose tolerance test; hormone inhibitor; hormone metabolism; hormone receptor; hormone regulation /control mechanism; human subject; hyperinsulinism; hypoglycemia; hypoglycemic agents; incretin hormone; laboratory mouse; metabolism disorder; patient oriented research; potassium channel; protein structure function; secretion

DESCRIPTION (provided by applicant): This proposal will provide the PI formal and informal training in translational research through mentors, coursework, seminars, and the pursuit of a patient-oriented research project examining the role of glucagon-like peptide-1 (GLP-1) in disorders of carbohydrate metabolism. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to nutrients. The mechanisms involved in GLP-1 secretion are complex, but similarities between the pancreatic a-cells and the L-cells point to a role of KATP channels in GLP-1 secretion. The beneficial physiologic and pharmacologic effects of GLP-1 are well established, less is known about the potential hypoglycemic effects of this peptide in pathologic conditions. The studies proposed here will examine the role of GLP-1 in two hypoglycemic disorders affecting children. These disorders are characterized by dysregulated insulin secretion resulting in severe hypoglycemia and neurodevelopmental sequelae if untreated. Our overall hypothesis is that abnormal GLP-1 secretion resulting from dysfunctional nutrient sensing in L-cells plays a role in these disorders. In Aim 1 we will examine GLP-1 secretion in children with congenital hyperinsulinism due to mutations in the KATP channel and determine whether inactivation of the GLP-1 receptor by a null mutation or by infusion of an antagonist, Ex9-39, significantly raises blood glucose in mice with an inactivating mutation of the KATP channel. In Aim 2 we will examine the role of GLP-1 in post-prandial hypoglycemia after Nissen fundoplication. Relevance: The proposed studies are key to the understanding of the pathogenesis of these disorders and will establish the basis for the potential therapeutic use of GLP-1 receptor antagonists for their treatment. Given the lack of effective medical therapies for these conditions, the potential use of GLP-1 receptor antagonist to control the hypoglycemia could have a significant effect on morbidity and long term outcome in this patient population. The PI, whose primary career goal is to become a translational researcher in the area of carbohydrate metabolism, will use this study as a mechanism for career development: 1) to solidify her skills as a clinical and laboratory investigator by working with experts in this area of research, 2) to participate in formal education in clinical and translational research at The University of Pennsylvania,and 3) to continue education in diabetes and endocrinology through local and national seminars.

描述（由申请人提供）： 该提案将通过导师，课程，研讨会以及对患者的研究项目进行转化研究的正式和非正式培训，以研究糖水代谢疾病中胰高血糖素样肽-1（GLP-1）的作用。 。 GLP-1是肠L细胞对营养物质分泌的肠降血糖素激素。 GLP-1分泌所涉及的机制很复杂，但是胰腺A细胞和L细胞之间的相似性指向KATP通道在GLP-1分泌中的作用。 GLP-1的有益生理和药理学作用已经确定，对这种肽在病理状况中的潜在降血糖作用的了解鲜为人知。这里提出的研究将研究GLP-1在两种影响儿童的降血糖疾病中的作用。这些疾病的特征是胰岛素分泌失调，导致严重的低血糖和神经发育后遗症，如果未经治疗。我们的总体假设是，L细胞中营养功能失调的营养感应引起的异常GLP-1分泌在这些疾病中起作用。在AIM 1中，我们将检查由于KATP通道中突变引起的先天性超胰岛素症儿童的GLP-1分泌，并确定是否通过无效突变使GLP-1受体失活或通过输注拮抗剂，EX9-39显着提高血液葡萄糖在KATP通道失活突变的小鼠中。在AIM 2中，我们将检查GLP-1在Nissen底索后的后诊断低血糖中的作用。相关性：拟议的研究是理解这些疾病发病机理的关键，并将为GLP-1受体拮抗剂进行治疗的潜在治疗使用建立基础。鉴于缺乏针对这些疾病的有效医疗疗法，因此可能使用GLP-1受体拮抗剂来控制低血糖可能会对该患者人群的发病率和长期结局产生重大影响。 PI的主要职业目标是成为碳水化合物代谢领域的转化研究人员，它将将此研究用作职业发展的机制：1）通过与该领域的专家合作来巩固她作为临床和实验室研究人员的技能研究，2）参加宾夕法尼亚大学临床和转化研究的正规教育，以及3）通过本地和国家研讨会继续接受糖尿病和内分泌学教育。