(Press-News.org) NEW YORK, NY (April 6, 2015) --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 today in the online edition of the Journal of Clinical Investigation.
"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."
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 Dr. 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 Dr. 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."
INFORMATION:
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).
The study was funded by grants from the American Heart Association (13POST16810041), the Schaefer Foundation, the Phillip Foundation, and the National Institutes of Health (R01HL061503, R01HL102040, and R01AR060037).
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.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.
MAYWOOD, IL - In 1993, neurologists Harold P. Adams Jr., MD, and Jose Biller, MD, and colleagues proposed a new way to classify strokes.
It became known as the TOAST classification.
Twenty-two years later, the TOAST classification remains an effective and easy-to-use system that is routinely employed in stroke studies around the world, Drs. Adams and Biller report in the journal Stroke, published online ahead of print.
Dr. Adams is a professor of neurology and director of Cerebrovascular Disease at the University of Iowa Carver College of Medicine. Dr. Biller is chair ...
Yes, while breastfeeding is the optimal first food for a baby, it's not as simple to say that it will protect all children from becoming obese. Recent studies show that factors such as whether a child's mother is obese, the quality of her milk and the socio-economic conditions a baby is born into also have an influence. This is according to Jessica Woo and Lisa Martin of the Cincinnati Children's Hospital Medical Center in the US, who reviewed relevant breastfeeding studies in Springer's journal Current Obesity Reports.
Because it is notoriously difficult to treat obesity, ...
Conduction and thermal radiation are two ways in which heat is transferred from one object to another: Conduction is the process by which heat flows between objects in physical contact, such as a pot of tea on a hot stove, while thermal radiation describes heat flow across large distances, such as heat emitted by the sun.
These two fundamental heat-transfer processes explain how energy moves across microscopic and macroscopic distances. But it's been difficult for researchers to ascertain how heat flows across intermediate gaps.
Now researchers at MIT, the University ...
MISSOULA - University of Montana researchers have good news for endurance athletes hankering for a burger and fries after an intense workout: Dig in.
In moderation, that is.
A new study, recently published by the International Journal of Sport Nutrition and Exercise Metabolism, found there was no significant difference in glycogen recovery when cyclists ate fast food after a workout versus when they ingested traditional sports supplements such as Gatorade, Powerbar and Clif products.
Brent Ruby, director of UM's Montana Center for Work Physiology and Exercise Metabolism, ...
Elder abuse is common, affecting an estimated 5%-10% of seniors; raising awareness among physicians is key to helping address the issue, according to a review in CMAJ (Canadian Medical Association Journal).
Although there is little evidence on screening for elder abuse and effective interventions, there should not be inaction on the part of health care professionals.
"Despite the lack of robust evidence to support recommendations, clinicians still need an approach to this relatively common problem," writes Dr. Xuyi Mimi Wang, a geriatric medicine fellow at McMaster ...
In rare cases, children can develop anaphylactic allergies to previously tolerated foods after receiving blood products via transfusion, report the authors of a case study published in CMAJ (Canadian Medical Association Journal).
"It is very unusual to identify someone who experienced passive transfer of allergy from blood products," says Dr. Julia Upton, The Hospital for Sick Children (SickKids), Toronto, Ontario. "Importantly, this condition has an excellent prognosis and typically resolves within a few months."
Blood donors who have food allergies can transfer immunoglobulin ...
Although sexual dysfunction is not a specific symptom of posttraumatic stress disorder (PTSD), it is a frequent complaint among trauma survivors. The Journal of Sexual Medicine review finds that PTSD-related biological and cognitive processes may contribute to the development of sexual dysfunction following traumatic stress.
The authors note that trauma exposure can profoundly rupture an individual's sense of safety and the ability to trust and feel connected to others. It may result in an association of arousal with threat.
"It is clear that PTSD is associated with ...
WASHINGTON, D.C. - The gases used to knock out surgery patients are accumulating in the Earth's atmosphere, where they make a small contribution to climate change, report scientists who have detected the compounds as far afield as Antarctica. Over the past decade, concentrations of the anesthetics desflurane, isoflurane and sevoflurane have been rising globally, the new study finds.
Like the well-known climate warmer carbon dioxide, anesthesia gases allow the atmosphere to store more energy from the Sun. But unlike carbon dioxide, the medical gases are extra potent in ...
In a recent study, females with eating disorders in late adolescence were more likely to have lower levels of educational attainment and personal income in early adulthood. They were also less likely to own a home. These associations were not seen in males.
Disordered eating behaviors may set some individuals on a different trajectory whereby they do not have the same life chances or opportunities for success in adulthood.
"Although the negative physical and mental health consequences of eating disorders have been well documented, much less is known about the adult ...
Sustainable rooftop technologies--including green roofs, white roofs, and solar photovoltaic panels--can provide great environmental benefits, but studies of these technologies often look only at their use in hot climates and do not assess their full environmental consequences.
A new study that compares the technologies in the cold Canadian climate shows that photovoltaic panels demonstrate the highest environmental performance in all impact categories considered and is the preferred option from an environmental perspective. Green roofs result in fewer beneficial environmental ...
