Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets

描述（由申请人提供）：KATP通道失活突变导致最常见和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，需要胰切除术来控制低血糖并防止永久性脑损伤。本研究的目的是通过检测KATPHI患儿胰岛的燃料代谢和刺激-分泌偶联来阐明KATPHI的ß-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触发途径的失调，而且还会产生继发性后果，通过触发和放大途径严重扰乱葡萄糖和氨基酸代谢，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特定目的中进行检验：目的1描述燃料代谢和燃料介导的胰岛素释放在人类胰岛中与KATP通道失活突变的特征，并检查细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。目的2侧重于研究代谢和camp介导的胰岛素分泌在人KATPHI胰岛能量生产框架内的放大。目的3研究了KATPHI胰岛和正常胰岛之间基因表达的差异，并整合了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率相关。自从发现这种疾病的分子基础以来，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治疗的发展。因此，对于携带最严重突变的儿童，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，反过来，这将有助于理解导致2型糖尿病的进行性ß-细胞衰竭的机制。因此，这些研究可能会导致高胰岛素血症和糖尿病治疗的新靶点的确定。

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.