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Calcium release channel RyR2 regulates insulin release and glucose homeostasis.

The Journal of clinical investigation (2015-04-07)
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

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.

Product Number
Product Description

Glybenclamide, ≥99% (HPLC)
Glyburide, meets USP testing specifications
Methyl pyruvate, 90%, technical grade
L-Leucine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%
L-Leucine, reagent grade, ≥98% (HPLC)
L-Leucine, BioUltra, ≥99.5% (NT)
L-Leucine, 99%, FG
L-Leucine, Vetec, reagent grade, ≥98%