Calcium and the physiology of diabetes

2型糖尿病(T2 DM)是世界范围内的一个主要健康问题，而且患病率还在不断上升。 目前的治疗方法有潜在的危及生命的副作用。更好地理解分子 T2 DM的潜在机制可能会导致治疗的改进。钙(Ca~(2+))在体内起关键作用。 朗格罕胰岛β细胞的胰岛素分泌。这个项目的重点是阐明 导致胰岛素分泌受损的钙调节改变的新机制。我们展示了 在一种罕见的遗传性疾病中，细胞内钙离子通过突变型2型兰尼定受体/钙泄漏 胰腺β细胞释放通道(RyR2)与糖耐量异常和胰岛素降低有关 分泌物。该项目的目标是使用几种T2 DM的小鼠模型来确定 观察到胰岛素分泌受损与RyR2介导的细胞内钙泄漏有关 不同2型糖尿病模型中的泛化现象。该方法将侧重于检查 RyR2，一种位于内质网(ER)上的钙释放通道，包括 胰腺β细胞，在胰岛素释放方面采用生化、生物物理和代谢试验。RyR2可以成为 由于基因突变或翻译后修饰(主要是氧化、亚硝化和 磷酸化)，所有这些都会损害通道的稳定关闭，导致病理性的细胞内 CA2泄漏。我们的目标是验证这样一种假设，即内质网钙离子通过RyR2“泄漏”导致胰岛素受损 2型糖尿病患者的分泌物。其理论基础是基于我们最近的发现，患有泄漏突变RyR2的患者 运动性猝死的途径和遗传性(儿茶酚胺能多态 室性心动过速(CPVT)有糖耐量试验(GTT)异常和胰岛素水平降低。 在申请人的实验室中培育的携带CPVT RyR2突变的敲入小鼠具有ER CA2泄漏、GTT异常和胰岛素水平降低，就像CPVT患者一样。目标是：1确定 泄漏的RyR2通道如何导致线粒体功能障碍和胰岛素释放减少。 RyR2通道功能障碍导致2型糖尿病小鼠胰岛素分泌受损？ 此外，我们将评估用一种新的修复漏水的药物进行药物治疗 RyR2通道，或修复泄漏的RyR2通道的基因治疗，改善钙信号转导和胰岛素 不同2型糖尿病模型的分泌物？该项目的目标将是在 内质网钙泄漏、内质网应激、线粒体功能障碍、胰岛素分泌减少和糖耐量异常 具有显著的翻译意义，因为Leaky RyR2可能代表着一种新的治疗靶点 2型糖尿病的治疗。

Type 2 diabetes mellitus (T2DM) is a major health concern worldwide, and the prevalence is increasing. Current therapeutics have potentially life-threatening side-effects. A better understanding of the molecular mechanisms underlying T2DM could lead to improved therapy. Calcium (Ca2+) plays a key role in the insulin secretion from pancreatic β cells in the islets of Langerhans. This project focuses on elucidating novel mechanisms underlying altered Ca2+ regulation that contribute to impaired insulin secretion. We show that in a rare genetic disorder intracellular Ca2+ leak via mutant type two ryanodine receptor/calcium release channels (RyR2) in pancreatic β cells is associated with glucose intolerance and decreased insulin secretion. The goal of this project is to use several murine models of T2DM to determine whether the observation that impaired insulin secretion is linked to RyR2-mediated intracellular Ca2+ leak is a generalized phenomenon in diverse models of T2DM. The approach will focus on examining the function of RyR2, a Ca2+ release channel located on the endoplasmic reticulum (ER) of many cell types including pancreatic β cells, in insulin release using biochemical, biophysical and metabolic tests. RyR2 can become leaky either due to genetic mutations or post-translational modifications (chiefly oxidation, nitrosylation and phosphorylation) all of which can impair stable closing of the channel resulting in pathological intracellular Ca2+ leak. The goal is to test the hypothesis that ER Ca2+ “leak” via RyR2 contributes to impaired insulin secretion in T2DM. The rationale is based on our recent finding that patients with leaky mutant RyR2 channels and an inherited form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia, CPVT) have abnormal glucose tolerance tests (GTT) and reduced insulin levels. Knock-in mice developed in the applicant’s laboratory harboring these CPVT RyR2 mutations have ER Ca2+ leak, abnormal GTT and reduced insulin levels, just like CPVT patients. The aims are: 1 Determine how leaky RyR2 channels cause mitochondrial dysfunction, and reduced insulin release.; 2) Does RyR2 channel dysfunction contribute to impaired insulin secretion in murine models of T2DM? Furthermore we will assess whether pharmacologic treatment with a new class of rycal drugs that fix leaky RyR2 channels, or genetic treatment that fixes leaky RyR2 channels, improves Ca2+ signaling, and insulin secretion in diverse models of T2DM? The goal of the project will be to provide mechanistic links between ER Ca2+ leak, ER stress, mitochondrial dysfunction, reduced insulin secretion and glucose intolerance, and has significant translational implications as leaky RyR2 may represent a novel therapeutic target for the treatment of T2DM.