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

描述(由申请人提供)： 这项建议将通过导师、课程作业、研讨会和一个以患者为导向的研究项目来为PI提供正式和非正式的翻译研究培训，研究GLP-1在碳水化合物代谢紊乱中的作用。胰升糖素-1是一种由肠道L细胞对营养物质作出反应而分泌的胰岛素激素。参与GLP-1分泌的机制很复杂，但胰腺a细胞和L细胞的相似之处表明KATP通道在GLP-1分泌中起作用。GLP-1的有益生理和药理作用已得到充分证实，但对其在病理条件下的潜在降血糖作用知之甚少。这里提出的研究将检验GLP-1在影响儿童的两种低血糖疾病中的作用。这些疾病的特点是胰岛素分泌失调，如果不治疗会导致严重的低血糖和神经发育后遗症。我们的总体假设是，L细胞的营养感知功能障碍导致的GLP-1分泌异常在这些疾病中发挥了作用。在目标1中，我们将检测由于KATP通道突变导致的先天性高胰岛素血症儿童的GLP-1分泌，并确定通过零突变或注射拮抗剂Ex9-39使GLP-1受体失活是否会显著提高KATP通道失活突变小鼠的血糖。在目标2中，我们将研究GLP-1在Nissen胃底折叠术后餐后低血糖中的作用。相关性：拟议的研究是了解这些疾病发病机制的关键，并将为GLP-1受体拮抗剂治疗这些疾病的潜在治疗用途奠定基础。鉴于这些疾病缺乏有效的药物治疗，潜在地使用GLP-1受体拮抗剂来控制低血糖可能会对这类患者的发病率和长期预后产生重大影响。PI的主要职业目标是成为碳水化合物代谢领域的翻译研究人员，她将利用这项研究作为职业发展的机制：1)通过与该研究领域的专家合作，巩固她作为临床和实验室研究人员的技能；2)参加宾夕法尼亚大学临床和翻译研究的正规教育；以及3)通过地方和国家研讨会继续糖尿病和内分泌学教育。

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.