A cellular defect that can impair the body’s ability to handle high glucose levels and could point the way to a potential new treatment for diabetes has been identified by Columbia University Medical Center (CUMC) researchers. The CUMC team found that ryanodine receptor type 2 (RyR2) calcium channels in insulin-producing cells play an important and previously underappreciated role in glucose balance.

RyR2 channels control intracellular calcium release. When leaky, they were found to reduce insulin release from the pancreas, resulting in high blood sugar levels in a test that measures the ability to regulate glucose. The researchers also demonstrated, in a mouse model of diabetes, that these leaks can be stopped and glucose levels normalized with an experimental drug called Rycal. The findings were published in the online edition of the Journal of Clinical Investigation. http://www.jci.org/

“We’ve known that calcium in the pancreatic beta cells plays a significant role in regulating insulin secretion, but calcium levels were thought to be controlled largely by the entry of calcium into the cell,” said senior author Andrew R. Marks, MD, professor and chair of physiology and cellular biophysics. “It turns out that there’s another mechanism in pancreatic beta cells that also controls calcium. This mechanism involves RyR2 channels, and leaks in these channels can lead to impaired glucose tolerance. These findings open up a whole new area of research into the molecular underpinnings of prediabetes and diabetes and point to potential therapeutic targets.”

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The CUMC researchers were initially studying a rare form of exercise-induced arrhythmia called catecholaminergic polymorphic ventricular tachycardia (CPVT), which can be caused by mutations in the RyR2 gene. “When we generated murine models of CPVT that harbor mutations in the RyR2 channels that make them leaky, we observed that they weren’t secreting enough insulin in response to glucose,” said lead author Gaetano Santulli, MD, PhD, a cardiologist working in Dr. Marks’ lab. “Since RyR2 channels are also expressed in pancreatic cells, we wondered whether they were mechanistically contributing to the glucose imbalance.”

To learn more, the researchers performed glucose tolerance tests on 27 CPVT patients with known mutations that make the RyR2 channels leaky. Many of these individuals exhibited reduced serum insulin levels and higher-than-normal blood sugar following a glucose challenge—a novel finding in this type of patient. “This was completely unexpected, and it suggested we were on to something important in terms of understanding diabetes,” said Marks, who is also the Clyde and Helen Wu Professor of Medicine and founding director of the Helen and Clyde Wu Center for Molecular Cardiology.

The researchers then turned back to the mouse models of CPVT, in an effort to determine what role, if any, RyR2s might play in impaired glucose tolerance. “Pancreatic beta cells were found to have leaky RyR2s, which were disrupting the function of mitochondria that provide cells with energy required for insulin release. The dysfunction was consistent with mitochondrial alterations that have been described in pancreatic beta cells from patients with type 2 diabetes,” said Santulli.

The researchers then tested the effects of a Rycal (an experimental drug that Dr. Marks’ team has shown can stop RyR2 leak) on CPVT mice with RyR2 mutations and on type 2 diabetic mice. The drug improved insulin secretion and glucose tolerance in both mouse models.

“The advantage of a Rycal is that many drugs now used to treat type 2 diabetes increase the risk for low blood sugar and for heart disease,” said Dr. Marks. “Based on the mechanism of action of Rycals, we would not expect this drug to cause either of these. Also, Rycals are currently being tested in patients with heart disease and muscle disorders and have a good safety record so far.”

The paper is titled, “Calcium release channel RyR2 regulates insulin release and glucose homeostasis.” The other contributors are: Gennaro Pagano (Imperial College, London, UK, University of Molise, Campobasso, Italy, and Federico II University, Naples, Italy), Celestino Sardu (Leiden University Medical Center, Leiden, Netherlands, Second University of Naples, Naples, Italy, and Catholic University of the Sacred Heart, John Paul II Foundation for Research and Treatment, Campobasso, Italy), Wenjun Xie (CUMC), Steven Reiken (CUMC), Salvatore Luca D’Ascia (Department of Cardiology and Arrhythmology, Clinical Institute Città Studi Hospital, Milan, Italy), Michele Cannone (Giuseppe Tatarella Hospital, Cerignola, Foggia, Italy), Nicola Marziliano (Niguarda Ca’ Granda Hospital, Milan, Italy, and University Hospital of Parma, Parma, Italy), Bruno Trimarco (Federico II University), Theresa A. Guise (Indiana University School of Medicine, Indianapolis, Indiana), and Alain Lacampagne (14U1046 INSERM, UMR 9214, CNRS, CHRU Montpellier, Montpellier, France).

Dr. Marks is a consultant and board member of ARMGO Pharma, Inc., which is targeting RyR channels for therapeutic purposes. The other authors declare no financial or other conflicts of interest.

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Ontario Health Minister Eric Hoskins recently announced government support of a future satellite dialysis centre at Etobicoke General Hospital.

Etobicoke resident Robert Johnstone is one of a “significant number of patients” served by Etobicoke General who will soon access dialysis closer to home rather than traveling three times a week to Brampton Civic Hospital for treatment, hospital officials said.

“This new satellite dialysis centre will help to ease a significant burden for patients suffering with kidney disease who will soon be able to access services closer to home,” Hoskins, an MD and PhD, said in a statement.

“Today’s announcement demonstrates our government’s commitment to putting patients first, connecting them with quality services in the community.”

William Osler Health System, which operates Etobicoke General and Brampton Civic hospitals, is one of 26 Chronic Kidney Disease Programs across Ontario. Last year, it saw more than 72,000 patient visits at Brampton Civic Hospital.

As need grows for dialysis services in Etobicoke, hospital officials said the new satellite dialysis centre will help improve patient experience and support “Osler’s vision of providing patient-centred health care without boundaries.”

“The satellite dialysis centre aligns with Ontario’s Action Plan for Health Care — “Patient’s First” by providing local residents with care closer to home,” Maria Britto, chair of the Central West LHIN board of directors, said in a statement.

The future dialysis centre will include 36 stations and provide vital pre-dialysis treatment and haemodialysis for patients, along with home dialysis training, hospital officials said.

It will be located in the soon-to-be-constructed ancillary services building at Etobicoke General. That 200,000-square-foot medical building will house a number of outpatient programs and services, including seniors’ wellness, mental health and addiction, COPD and cardiac.

“Osler’s new satellite dialysis centre will offer treatment closer to home for our renal patients and greater access to the services this community needs most,” Osler president and CEO Matthew Anderson said in a statement.

“This investment is vital to Osler and serves to create fundamental stepping stones that allow us to press forward with our exciting transformation.”

The ancillary services building, which will house the dialysis centre, will be built first, followed by Etobicoke General’s new patient tower, Ann Ford, Osler’s vice-president of development and information technology, told the Guardian last month.

Last month, Osler named the three short-listed proponent teams to bid on the build of its new four-storey patient tower at Etobicoke General.

EllisDon Infrastructure Healthcare, Etobicoke Healthcare Partnership and Plenary Health were chosen in a competitive process to respond to a Request for Proposals (RFP) to be issued later this month to design, build, finance and maintain the tower.

A larger, state-of-the-art emergency department, four times larger Intensive Care and Critical Care Units and larger, natural light-filled patient rooms to accommodate family, medical teams and equipment will be features of the 250,000-square-feet space tower.

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