The type 2 ryanodine receptor (RyR2) is an ER-localized calcium release channel that is present in many cell types, including cardiomyocytes and pancreatic β cells. While calcium flux is pivotal for insulin secretion by pancreatic β cells, it is unclear if RyR2 plays a role in insulin release. Individuals with the rare human disease catecholaminergic polymorphic ventricular tachycardia (CPVT), which often first manifests as exercised-induced sudden death, harbor mutations that render the RyR2 channel “leaky”. Gaetano Santulli and colleagues at Columbia University Medical Center reveal that individuals with CPVT also present with glucose intolerance and impaired insulin secretion. Transgenic expression of CPVT-associated RyR2 channels in a murine model (CPVT mice) revealed that these channels are oxidized, nitrosylated, and leaky not only in the heart but also in pancreatic β cells, leading to increased ER stress, mitochondrial dysfunction, and profound glucose intolerance. Moreover, treatment of CPVT mice with a RyR2-stabilizing drug prevented intracellular calcium release, improved glucose tolerance, and increased insulin secretion. The authors further evaluated the pharmacological effects of this drug in both human islets from patients with type 2 diabetes and in established murine models of diabetes. The results of this study identify a link between RyR2-dependent calcium leak and β cell dysfunction and raise the possibility that the relationship between diabetes mellitus and cardiovascular disease might be more complex than previously appreciated. The accompanying electron micrograph depicts the mitochondrial dysmorphology (green) that occurs in a pancreatic β cell harboring CPVT-associated RyR2, which is located on the endoplasmic reticulum (yellow). Insulin granules (blue) can be seen throughout the cytoplasm. Image credit: Dr. Gaetano Santulli, MD, PhD (Columbia University Medical Center).
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 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.
Gaetano Santulli, Gennaro Pagano, Celestino Sardu, Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia, Michele Cannone, Nicola Marziliano, Bruno Trimarco, Theresa A. Guise, Alain Lacampagne, Andrew R. Marks