Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets

KATP-高胰岛素血症人胰岛的燃料代谢和胰岛素分泌

基本信息

批准号：
8630007
负责人：
Diva D. De Leon
金额：
$ 37.88万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630007
关键词：
Affect Amino Acids Biology Blood Glucose Brain Injuries Calcium Calcium Channel Calcium Signaling Calmodulin Cell membrane Cells Characteristics Child Citric Acid Cycle Coupling Cyclic AMP Defect Development Diabetes Mellitus Disease Failure Fasting Functional disorder Gene Expression Generations Genes Glucose Glutamine Glycolysis Goals Hereditary Disease Human Hyperinsulinism Hypoglycemia Insulin Lead Measures Mediating Medical Metabolic Metabolism Molecular Molecular Profiling Mus Mutation Neurodevelopmental Impairment Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Pancreatectomy Pathway interactions Persistent Hyperinsulinemia Hypoglycemia of Infancy Phenotype Play Production Proteins Regulation Regulatory Pathway Respiration Role Second Messenger Systems Severities Signal Transduction Stimulus Testing Water base diabetes risk effective therapy genome-wide improved inhibitor/antagonist insulin secretion islet mouse model novel prevent public health relevance response second messenger stable isotope transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Inactivating mutations in KATP channels cause the most common and severe form of congenital hyperinsulinism (KATPHI). Children with KATPHI are usually unresponsive to medical therapy and require pancreatectomy to control the hypoglycemia and prevent permanent brain damage. The goal of this proposal is to elucidate the ¿-cell pathophysiology in KATPHI through the examination of fuel metabolism and stimulus-secretion coupling in islets isolated from children with KATPHI. Our overall hypothesis is that disturbances in KATP channels function result not only in dysregulation of the triggering pathway of insulin release, but also have secondary consequences that drastically disturb glucose and amino acid metabolism and alter fuel-stimulated insulin secretion through both the triggering and the amplification pathway. This hypothesis will be examined in three related and overlapping specific aims: Aim 1 characterizes fuel metabolism and fuel-mediated insulin release in human islets with inactivating mutations in KATP channels and examines the role that elevated cytosolic calcium plays in determining the fate of metabolic fuels in these islets. Aim 2 focuses on examining the metabolic and cAMP-mediated amplification of insulin secretion within the framework of energy production in human KATPHI islets. Aim 3 examines the differences in gene expression between KATPHI islets and normal islets and integrates the metabolic and transcriptional profile of these islets to understand the mechanisms underlying the differences in fuel metabolism and insulin secretion. KATPHI is a severe genetic disorder associated with high rates of neurodevelopmental impairment. It has been almost 20 years since the discovery of the molecular basis of this condition. However, the incomplete understanding of the pathophysiology underlying the dysregulated insulin secretion has precluded the development of effective therapies. Thus, outcomes with current treatment approaches continue to be suboptimal for children carrying the most severe mutations. Our study aims at examining the pathophysiology within the framework of the energy production/insulin secretion relationship to identify new targets for therapy. This study will improve our understanding of the mechanisms and second messengers mediating the amplifying pathway of insulin secretion, which in turn, will be helpful for understanding the mechanisms implicated in the progressive ¿-cell failure that leads to type 2 diabetes. Thus, these studies may lead to the identification of novel targets for therapy not only for hyperinsulinism but also for diabetes.

描述（由适用提供）：KATP通道中的灭活突变会导致先天性超胰岛素症（Katphi）最常见和最严重的形式。患有Katphi的儿童通常对医疗治疗无反应，需要胰腺切除术来控制低血糖并防止永久性脑损伤。该提案的目的是通过检查Katphi儿童分离的胰岛中的燃料代谢和刺激 - 分泌耦合来阐明Katphi中的细胞病理生理学。我们的总体假设是，KATP通道功能的扰动不仅导致胰岛素释放的触发途径失调，而且还会带来次要后果，这些后果在拖曳的葡萄糖和氨基酸代谢中会造成触发和扩增途径。该假设将在三个相关和重叠的特定目的中进行检查：AIM 1表征了燃料代谢和燃料介导的胰岛素释放，在KATP通道中灭活突变的人类胰岛释放，并检查了升高细胞质钙在确定这些小便中代谢燃料的命运方面发挥的作用。 AIM 2专注于研究人类Katphi Islet能源生产框架内胰岛素分泌的代谢和介导的扩增。 AIM 3检查了Katphi胰岛与正常胰岛之间基因表达的差异，并整合了这些小岛的代谢和转录特征，以了解燃料代谢和胰岛素分泌差异的机制。 Katphi是一种严重的遗传疾病，与高神经发育障碍率有关。自从发现这种情况的分子基础以来已经将近20年了。然而，对失调的胰岛素分泌基础的病理生理学的不完全理解排除了有效疗法的发展。对于携带最严重突变的儿童而言，采用当前治疗方法的结果继续是最佳的。我们的研究旨在检查能量生产/胰岛素分泌关系框架内的病理生理学，以识别治疗的新靶标。这项研究将提高我们对介导胰岛素分泌途径的机制和第二使者的理解，这反过来又有助于理解渐进式失败中实施的机制，导致2型糖尿病。这是这些研究可能导致鉴定新的治疗靶标，不仅用于过度胰岛素主义，而且还可以鉴定出糖尿病的治疗。