Evaluating verapamil

Blood pressure drug verapamil has been found to lower levels of TXNIP, a protein linked to diabetes

Kelsey Kaustinen
BIRMINGHAM, Ala.—Drug repurposing consists of revisiting approved therapeutics to explore their potential in other indications, and one of the latest drugs that might have potential beyond its initial indication is verapamil, which is indicated for the treatment of high blood pressure, angina and arrhythmia. Researchers at the University of Alabama at Birmingham (UAB) have studied beta cells for years and discovered that high blood sugar causes the body to overproduce of the protein TXNIP, which is increased in beta cells in response to diabetes. Overly high levels of this protein in the pancreatic beta cells leads to cell death and inhibits the body's ability to produce insulin, which contributes to the progression of diabetes. While investigating verapamil, the researchers found the drug can lower TXNIP levels in beta cells in mice, effectively eliminating the disease in the mouse models.
 
“Currently, we can prescribe external insulin and other medications to lower blood sugar, but we have no way to stop the destruction of beta cells, and the disease continues to get worse,” Fernando Ovalle, M.D., director of the Comprehensive Diabetes Clinic and co-principal investigator, commented. “If verapamil works in humans, it would be a truly revolutionary development in a disease affecting more people each year to the tune of billions of dollars annually.”
 
To pursue the potential of this approach, UAB researchers will initiate a clinical trial next year to determine whether these results can be reproduced in humans. The trial, “the repurposing of verapamil as a beta cell survival therapy in type 1 diabetes,” is being funded by a $2.1-million grant from the Juvenile Diabetes Research Foundation. The trial will seek to enroll 52 people ages 19 to 45 who are within three months of having received a diagnosis of type 1 diabetes. Participants will receive either verapamil or a placebo for one year while continuing with insulin pump therapy and will also receive a continuous glucose monitoring system to allow for 24/7 measuring of their blood sugar. In addition, patients' blood sugar control and ability to produce insulin will also be tracked, and the UAB clinic team will also utilize the c-peptide response test to measure beta cell insulin production and functional beta cell mass.
 
“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,” Anath Shalev, M.D., director of UAB's Comprehensive Diabetes Center and principal investigator of the upcoming verapamil 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.”
 
Beta cells play critical roles in both types 1 and 2 diabetes, and are lost in both forms of the disease due to programmed cell death.
 
“This trial is based on a well-known blood pressure medication that has been used for more than 30 years and is unlikely to have any severe side effects,” Shalev said. “This study is also backed by a lot of strong mechanistic data in different mouse models and human islets, and we already know the mechanisms by which verapamil acts. Finally, unlike any currently available diabetes treatment, the trial targets the patient’s own natural beta cell mass and insulin production.”
 
The UAB Comprehensive Diabetes Center is pursuing this new approach—the targeting of TXNIP—with the Alabama Drug Discovery Alliance, a partnership between the UAB School of Medicine and Southern Research Institute; the organizations are searching for small molecules capable of inhibiting TXNIP.
 
Diabetes is the seventh-leading cause of death in the United States, with 12.3 percent of Americans 20 and older living with diabetes and 37 percent with prediabetes. According to the American Diabetes Association, diabetes cost $245 billion in healthcare costs last year.

Kelsey Kaustinen

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