Santulli, GaetanoPagano, GennaroSardu, CelestinoXie, WenjunReiken, StevenD'Ascia, Salvatore LucaCannone, MicheleMarziliano, NicolaTrimarco, BrunoGuise, Theresa A.Lacampagne, AlainMarks, Andrew R.2015-07-212015-07-212015-04Santulli, G., Pagano, G., Sardu, C., Xie, W., Reiken, S., D’Ascia, S. L., ... & Marks, A. R. (2015). Calcium release channel RyR2 regulates insulin release and glucose homeostasis. The Journal of clinical investigation, 125(125 (5)), 0-0.https://hdl.handle.net/1805/6578The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a “leaky” RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.en-USPublisher PolicyRyR2insulin releasetype 2 diabetesglucose homeostasisArticle