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

• 批准号: 8852609
• 负责人: Diva D. De Leon
• 金额: $ 36.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852609
• 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; amino acid metabolism; 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; targeted treatment; transcriptome sequencing

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（由申请人提供）：KATP 通道失活突变会导致最常见和最严重的先天性高胰岛素血症 (KATPHI)。患有 KATPHI 的儿童通常对药物治疗没有反应，需要进行胰腺切除术来控制低血糖并防止永久性脑损伤。该提案的目标是通过检查从 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 的细胞病理生理学。我们的总体假设是，KATP 通道功能的紊乱不仅会导致胰岛素释放触发途径的失调，还会产生继发性后果，严重扰乱葡萄糖和氨基酸代谢，并通过触发和放大途径改变燃料刺激的胰岛素分泌。该假设将在三个相关且重叠的具体目标中进行检验：目标 1 描述了具有 KATP 通道失活突变的人类胰岛中的燃料代谢和燃料介导的胰岛素释放，并研究了胞质钙升高在决定这些胰岛中代谢燃料的命运中所起的作用。目标 2 重点检查人类 KATPHI 胰岛能量产生框架内的代谢和 cAMP 介导的胰岛素分泌放大。目标 3 检查 KATPHI 胰岛和正常胰岛之间基因表达的差异，并整合这些胰岛的代谢和转录谱，以了解燃料代谢和胰岛素分泌差异的潜在机制。 KATPHI 是一种严重的遗传性疾病，与高比例的神经发育障碍相关。自从发现这种病症的分子基础以来，已经过去了近 20 年。然而，对胰岛素分泌失调的病理生理学的不完全了解阻碍了有效疗法的开发。因此，对于携带最严重突变的儿童来说，目前的治疗方法的结果仍然不是最理想的。我们的研究旨在检查能量产生/胰岛素分泌关系框架内的病理生理学，以确定新的治疗靶点。这项研究将提高我们对介导胰岛素分泌放大途径的机制和第二信使的理解，进而有助于理解导致 2 型糖尿病的进行性β细胞衰竭所涉及的机制。因此，这些研究可能会导致确定新的治疗靶点，不仅可以治疗高胰岛素血症，还可以治疗糖尿病。