Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets

描述（由申请人提供）：KATP通道的失活突变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无反应，需要进行胰腺切除术以控制低血糖并防止永久性脑损伤。本提案的目的是通过检查从KATPHI儿童分离的胰岛中的燃料代谢和刺激-分泌偶联来阐明KATPHI中的胰岛细胞病理生理学。我们的总体假设是，KATP通道功能的紊乱不仅导致胰岛素释放的触发途径的失调，而且还具有次级后果，其通过触发途径和放大途径显著干扰葡萄糖和氨基酸代谢并改变燃料刺激的胰岛素分泌。这一假设将在三个相关和重叠的具体目标进行检查：目标1的特点燃料代谢和燃料介导的胰岛素释放在人类胰岛与失活突变的KATP通道，并检查的作用，升高的胞质钙在确定这些胰岛的代谢燃料的命运。目的2集中于在人KATPHI胰岛中能量产生的框架内检查胰岛素分泌的代谢和cAMP介导的扩增。目的3研究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机制。KATPHI是一种严重的遗传性疾病，与神经发育障碍的高发生率相关。自从发现这种情况的分子基础以来已经将近20年了。然而，对胰岛素分泌失调的病理生理学的不完全理解阻碍了有效疗法的开发。因此，目前治疗方法的结果对于携带最严重突变的儿童仍然是次优的。我们的研究旨在研究能量产生/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胰岛素分泌放大途径的机制和第二信使的理解，这反过来将有助于理解导致2型糖尿病的进行性胰岛细胞衰竭的机制。因此，这些研究可能会导致新的治疗目标的确定不仅对高胰岛素血症，而且对糖尿病。

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 ß-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 ß-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.