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<div class='row'> <div class='small-12 columns'> <h1>Intracellular calcium leak recasts β cell landscape </h1> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <p><p><img src="https://dm5migu4zj3pb.cloudfront.net/posts/file/359/May_B-_79273.jpg" style="width: 900px; height: 900px;" /></p> <p><span style="line-height: 1.6em;">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 </span><span style="line-height: 20.8000011444092px;">β</span><span style="line-height: 1.6em;"> 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 </span><span style="line-height: 20.8000011444092px;">β</span><span style="line-height: 1.6em;"> 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).</span></p> </p> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='published-at'> Published April 6, 2015, by Corinne Williams </span> <div> <p><a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/28"><span style='margin-right: 6px' class="label-specialty">Metabolism</span></a></p> </div> </div> </div> <div class='row'> <div class='small-12 columns' style='padding-bottom:12px;'> <h3>Related articles</h3> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/79273">Calcium release channel RyR2 regulates insulin release and glucose homeostasis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/79273">Gaetano Santulli, … , Alain Lacampagne, Andrew R. Marks</a> <a class='hide-for-small show-more' data-reveal-id='article33552-more' href='#'> <div class='article-authors'> Gaetano Santulli, … , Alain Lacampagne, Andrew R. Marks </div> </a> <span class='article-published-at'> Published April 6, 2015 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2015;<a id="article_metadata" href="http://www.jci.org/125/5">125(5)</a>:1968-1978. <a href="https://doi.org/10.1172/JCI79273">https://doi.org/10.1172/JCI79273</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/79273">Text</a> | <a href="/articles/view/79273/pdf">PDF</a> | <a class="CorrectionLink" href="/articles/view/84937">Corrigendum</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/51"><span class='label-article-type'> Research Article </span> </a><a href="/tags/15"><span class='label-specialty'> Cardiology </span> </a><a href="/tags/28"><span class='label-specialty'> Metabolism </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI79273' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article33552-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/79273">Calcium release channel RyR2 regulates insulin release and glucose homeostasis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/79273">Text</a></li> <li><a class="button tiny" href="/articles/view/79273/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>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.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>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</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>