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The type 2 ryanodine receptor (RyR2) is a [Ca.sup.2] release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic [beta] cells. In cardiomyocytes, RyR2-dependent [Ca.sup.2] 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 [beta] 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 [beta] cells from these animals revealed intracellular [Ca.sup.2] 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 [Ca.sup.2] 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., Introduction The molecular mechanisms underlying insulin secretion and glucose metabolism have not been fully elucidated (1-6). Numerous studies have demonstrated that calcium ([Ca.sup.2+]) plays a pivotal role in insulin secretion [...]