Calcium release channel RyR2 regulates insulin release 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

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114 Scopus citations

Abstract

The type 2 ryanodine receptor (RyR2) is a Ca<sup>2+</sup> release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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+</sup> 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.

Original languageEnglish (US)
Pages (from-to)1968-1978
Number of pages11
JournalJournal of Clinical Investigation
Volume125
Issue number5
DOIs
StatePublished - May 1 2015

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Santulli, G., Pagano, G., Sardu, C., Xie, W., Reiken, S., D'Ascia, S. L., Cannone, M., Marziliano, N., Trimarco, B., Guise, T. A., Lacampagne, A., & Marks, A. R. (2015). Calcium release channel RyR2 regulates insulin release and glucose homeostasis. Journal of Clinical Investigation, 125(5), 1968-1978. https://doi.org/10.1172/JCI79273