Intracellular calcium leak and mitochondrial dysfunction integrate diabetes and heart disease

The overall goal of my research is to determine the functional link connecting heart disease and type 2 diabetes mellitus (T2DM). Cardiovascular disease and diabetes represent major health concerns in US and worldwide. Whereas the association of TD2M with heart failure has been undoubtedly established, the reciprocal relationship, i.e. the increased risk of diabetes in patients with cardiovascular disorders, has been recently evidenced in the clinical scenario but the underlying molecular mechanisms remain essentially unclear. The present proposal will focus on the role of ryanodine receptor/Ca2+ release channel (RyR) in glucose homeostasis. Ca2+ plays a central role in insulin secretion and numerous studies have demonstrated that altered cellular Ca2+ homeostasis is a key contributor to impaired beta-cell function and survival in T2DM. However, according to the classical view of the glucose sensing machinery, insulin secretion largely depends on the depolarization of the plasma membrane and the subsequent voltage-activated Ca2+ influx from the extracellular space. The role of the mobilization of Ca2+ from the endoplasmic reticulum (ER) in response to glucose remains controversial. While the expression of RyR2 has been previously reported in pancreatic beta-cells, its functional role has not been fully dissected. Moreover, oxidative stress is well established in diabetes. The PI proposes to test the hypothesis that intracellular Ca2+ 'leak' via oxidized and leaky RyR2 channels contributes to impaired insulin secretion and the development of diabetes. The study has significant translational implications because leaky RyR2 may represent a novel therapeutic target for the treatment of T2DM using novel Rycal drugs, which prevent RyR2 leak by inhibiting the depletion of the stabilizing subunit calstabin2 (FKBP12.6). -Specific Aim 1: Characterize the role of RyR2 Ca2+ release channels in insulin release. Our preliminary data show that patients with catecholaminergic polymorphic venticular tachycardia (CPVT), and multiple genetic mouse (knockin) models of CPVT have abnormal glucose tolerance. -Specific Aim 2: Determine whether pharmacologic inhibition of intracellular Ca2+ leak improves glucose homeostasis in animal models of diabetes mellitus and heart failure. A small molecule prevents the loss of the RyR2 stabilizing subunit calstabin2 from RyR2 and stabilizes its closed state, inhibiting a pathologic leak. (AHA Program: Scientist Development Grant)