Diabetes is the seventh leading cause of death in the US, raising risks for heart attack, blindness, kidney disease and limb amputation. But researchers who have shown that a common blood pressure drug totally reverses diabetes in mice are about to begin a new clinical trial to see if it can do the same for humans. Diabetes affects 12.3% of Americans over the age of 20 and costs the nation $245 billion each year.
The researchers, from the University of Alabama at Birmingham (UAB) and led by Dr. Anath Shalev, have been working on this research for over a decade in UAB’s Comprehensive Diabetes Center.
They explain that their previous research has shown that high blood sugar causes an overproduction of a protein called TXNIP – which is increased within beta cells in response to diabetes. Too much TXNIP in pancreatic beta cells leads to their deaths, stopping the body’s efforts to produce insulin and further promoting diabetes.
UAB scientists have also uncovered that the drug verapamil, which is widely used to treat high blood pressure, irregular heartbeat and migraine headaches, can lower TXNIP levels in these beta cells — to the point that, when mouse models with established diabetes and blood sugars above 300 milligrams per deciliter were treated with verapamil, the disease was eradicate
The trial will test an approach different from any current diabetes treatment by focusing on promoting specialized cells in the pancreas called beta cells, which produce insulin the body needs to control blood sugar. UAB scientists have proved through years of research that high blood sugar causes the body to overproduce a protein called TXNIP, which is increased within the beta cells in response to diabetes, but had never previously been known to be important in beta cell biology. Too much TXNIP in the pancreatic beta cells leads to their deaths and thwarts the body’s efforts to produce insulin, thereby contributing to the progression of diabetes.
The UAB researchers have received a 3-year, $2.1 million grant from JDRF – the largest charitable supporter of type 1 diabetes research – to conduct a clinical trial in 2015 in humans.
“We have previously shown that verapamil can prevent diabetes and even reverse the disease in mouse models and reduce TXNIP in human islet beta cells, suggesting that it may have beneficial effects in humans as well,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and principal investigator of the verapamil clinical trial. “That is a proof-of-concept that, by lowering TXNIP, even in the context of the worst diabetes, we have beneficial effects. And all of this addresses the main underlying cause of the disease — beta cell loss. Our current approach attempts to target this loss by promoting the patient’s own beta cell mass and insulin production. There is currently no treatment available that targets diabetes in this way.”
The trial will enroll 52 people between the ages of 19 and 45 within three months of receiving a diagnosis of type 1 diabetes. Patients enrolled will be randomized to receive verapamil or a placebo for one year while continuing with their insulin pump therapy. In addition, they will receive a continuous glucose monitoring system that will enable them to measure their blood sugar 24 hours a day, seven days a week.
A first step
Shalev says the trial is a first step in the direction of such a novel diabetes treatment approach.
“While in a best-case scenario, the patients would have an increase in beta cells to the point that they produce enough insulin and no longer require any insulin injections — thereby representing a total cure — this is extremely unlikely to happen in the current trial, especially given its short duration of only one year,” Shalev said.
Shalev expects verapamil to have a much more subtle yet extremely important effect.
“We know from previous large clinical studies that even a small amount of the patient’s own remaining beta cell mass has major beneficial outcomes and reduces complications,” Shalev said. “That’s probably because even a little bit of our body’s own beta cells can respond much more adequately to very fine fluctuations in our blood sugar — much more than we can ever do with injections or even sophisticated insulin pumps.”
Because verapamil’s mode of action is different from current drugs or interventions, this opens up an entirely new field for diabetes drug discovery — one that UAB’s Comprehensive Diabetes Center is already engaged in with the Alabama Drug Discovery Alliance, a partnership between UAB’s School of Medicine and Southern Research Institute. The group is actively looking for small therapeutic molecules that inhibit TXNIP to protect the beta cells and treat diabetes.
“We want to find new drugs — different from any current diabetes treatments — that can help halt the growing, worldwide epidemic of diabetes and improve the lives of those affected by this disease,” Shalev said. “Finally, we have reason to believe that we are on the right track.”
SOURCES- University of Alabama at Birmingham, Youtube