Nicola Marziliano, Alain Lacampagne, Celestino Sardu, Andrew R. Marks, Bruno Trimarco, Wenjun Xie, Steven Reiken, Salvatore Luca D'Ascia, Gennaro Pagano, Theresa A. Guise, Michele Cannone, Gaetano Santulli, Columbia University Irving Medical Center (CUIMC), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' (DIA), University of Pisa - Università di Pisa, Department of Electrophysiology, Department of Physiology & Cellular Biophysics, Columbia University [New York], Department of Cardiology and Arrhythmology, 9Division of Cardiology, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Department of Advanced Biomedical Sciences, Division of Endocrinology, Indiana University [Bloomington], Indiana University System-Indiana University System, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Columbia University College of Physicians and Surgeons, University of Naples Federico II, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santulli, Gaetano, Pagano, Gennaro, Sardu, Celestino, Xie, Wenjun, Reiken, Steven, D'Ascia, SALVATORE LUCA, Cannone, Michele, Marziliano, Nicola, Trimarco, Bruno, Guise, Theresa A, Lacampagne, Alain, Marks, Andrew R., D'Ascia, Salvatore Luca, and Marks, Andrew R
The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic beta cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in beta 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 p 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 p 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.