November 9, 2014 | by Stephen Luntz (original source here)
Funding has been secured for a clinical trial of a drug that not only prevents mice from getting type I diabetes, but actually reverses the condition if it has already taken hold.
Verapamil has dangerous interactions with some other drugs. However, while side-effects such as nausea and swollen feet may be unpleasant, the dangers are seldom life threatening, and generally a better alternative to having diabetes. Such a history of long-term usage should shorten the clinical trial process and improve the chances of gaining regulatory approval.
The potential application to diabetes arises from the discovery by Dr. Anath Shalev of the University of Alabama, Birmingham (UAB) that verapamil lowers the level of the protein TXNIP in pancreatic beta cells.
Back in 2002, Shalev, then at the University of Wisconsin-Madison, began a search to find the gene that responded most strongly in the pancreas to excessive glucose levels. This turned out to be the TXNIP gene. Moreover, TXNIP’s full name is thioredoxin-interacting protein; high levels of thioredoxin have been shown to keep the pancreas’ insulin-producing islet beta cells alive.
“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,” Shalev said, announcing plans for the clinical trials.
Most recently, Shalev revealed that TXNIP can stimulate its own expression. “These findings support the notion,” Shaleve wrote, “that TXNIP levels rise over time, not only as a result of elevated blood glucose levels and/or endoplasmic reticulum stress, but also as part of a vicious cycle by which increased TXNIP levels lead to more TXNIP expression and thereby amplify the associated detrimental effects on beta-cell biology including oxidative stress, inflammation, and ultimately beta-cell death and disease progression.”
The JDRF funded trial will involve 52 newly diagnosed patients with diabetes, half of whom will be put on verapamil and half on a placebo. All patients will continue to receive insulin pump therapy. “That is a proof-of-concept that, by lowering TXNIP, even in the context of the worst diabetes, we have beneficial effects,” says Shalev. “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.”
Meanwhile Shalev is starting work on producing molecules with more targeted and efficient versions of verapamil’s effect on TXNIP.
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