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Patients with type 1 diabetes -- and their doctors -- dream of a life without insulin injections. Our long-term goal is to make that desire a reality, and we've started by looking for potential factors that were involved in the death of insulin-producing beta cells.
Our lab is targeting a specific protein, TXNIP, which seems to induce beta cell death when it's over-expressed.
The good news is that we may not have to wait for the painstakingly long process of developing a new drug to act on TXNIP. A cheap old calcium channel blocker may do the trick, at least for now.
In several studies, my colleagues at the UAB Comprehensive Diabetes Center and I demonstrated that TXNIP plays a central role in mediating the response of beta cells to stressful stimuli. We found that overexpression of this protein in beta cells occurs during the development of diabetes and, if left unchecked, leads to death of these cells. Conversely, we were able to show that reducing TXNIP levels in beta cells could prevent development of diabetes in mouse models.
Through our research, we noted that the the calcium channel blocker verapamil, used to treat hypertension and various heart conditions, could also lower TXNIP levels in beta cells. We showed that this drug could both prevent and reverse diabetes in mouse models.
Since verapamil is an FDA-approved drug with a clear safety profile, we were able to quickly advance this research to the clinical trial stage where we are testing the drug's effectiveness in patients who have recently (i.e. within 3 months) been diagnosed with T1D. In this current study, we are asking if verapamil can promote beta cell survival and slow progression of T1D, potentially reducing insulin requirements and improving glucose control in patients with the disease.
Several previous studies came into play in helping us identify verapamil as a potentially beneficial therapy for blocking TXNIP and preventing beta cell death. Our research team had noticed that, based on its ability to lower cellular calcium levels, use of verapamil is associated with a decrease in TXNIP levels in both mouse and human beta cells. Previously, we had also shown that genetic deletion of TXNIP in mouse models was able to prevent diabetes by promoting beta cell survival and beta cell function.
Based on this information, we tested the ability of oral verapamil to block TXNIP expression and reverse diabetes in already diabetic mice. While blood glucose got worse in the control group that didn't receive the drug, those receiving verapamil reduced their blood glucose to normal levels, had normal insulin-producing beta cells, and completely reversed their diabetes.
We do not expect such dramatic effects in our current human trial, and no reports of diabetes reversal are available despite some patients with diabetes receiving verapamil for other reasons. However, verapamil treatment is typically initiated later in the disease process when beta cell mass may already be severely compromised, and most studies focus on cardiovascular events rather than diabetes. Spinoff studies from the International Verapamil SR/Trandolapril Study (INVEST) show, however, that verapamil reduced the risk of new-onset type 2 diabetes, supporting a potential beneficial effect in humans.
The primary goal of the newly launched human clinical trial is to assess the safety and efficacy of using oral verapamil to prevent beta cell death, increase insulin production, and improve blood glucose control in patients with recent-onset T1D. The double-blind study will enroll approximately 52 volunteers between the ages of 19 and 45 who will be randomized to receive either verapamil or a placebo once a day for a year while continuing insulin pump therapy.
Researchers will track participants' C-peptide levels following meal ingestion (an indirect measure of beta cell function), as well as their blood sugar control and insulin requirements in order to measure any impact on their beta cell mass, function, and related insulin production. Recruitment of patients will continue until spring of 2016, and initial results from the trial are expected in early 2018.
If this trial suggests that verapamil can be effective at slowing progression of T1D and protecting beta cells, a larger trial will be needed to confirm the drug's usefulness in a broader population of individuals with T1D. It is also possible that the drug might need to be paired with other therapies to regenerate beta cells or provide more robust control of the immune system attack.
If successful, however, verapamil therapy would target the underlying cause of T1D -- beta cell loss -- which current treatments aren't able to do.
Anath Shalev, MD, is the director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham.
Type 1: Diabetes Discovery is a monthly blog post about basic science research, written by a JDRF-supported scientist.
Disclosures
Shalev is supported by JDRF.