Verapamil Hope for Reversal of Type 1 Diabetes

Pam Harrison

November 06, 2014

A first-of-its kind trial in patients with type 1 diabetes is scheduled to get under way next year, in which researchers will try to reverse the disease process by attempting to increase beta-cell mass with the help of a common cardiovascular medication.

The team has already shown that verapamil, often used to control hypertension and arrhythmias, can not only prevent type 1 diabetes in mice but reverse severe established diabetes as well, the lead researcher, Dr Anath Shalev (University of Birmingham, Alabama [UAB]), told a live newscast this week.

The human trial, entitled, "The repurposing of verapamil as a beta-cell survival therapy in type 1 diabetes," is expected to begin early in 2015 after more than a decade of research suggests that verapamil may be able to downregulate a key promoter of type 1 diabetes and bolster whatever dysfunctional beta cells remain in the pancreas, said Dr Shalev.

The study will initially last a year.

"We…know that treatment definitely creates an environment where beta cells are allowed to survive, and their survival is a major factor in potentially improving insulin production, so our hope is that we'll see a similar effect in type 1 diabetes patients to what we have seen in our mice models."

From Bench to Bedside

Dr Shalev explained that over a decade ago, the UAB team was able to identify a protein called thioredoxin-interacting protein (TXNIP), which is dramatically increased in human islet cells in response to high glucose levels.

Since it's known that hyperglycemia is toxic to beta cells, "we hypothesized that TXNIP might be involved in beta-cell death associated with diabetes."

It is thus "highly conceivable" that even short-term postprandial glucose excursions — as are often seen in prediabetes — may lead to a gradual, cumulative increase in TXNIP expression before any onset of overt diabetes, she observes.

Furthermore, insulin resistance or any increased demand on the beta cell may also lead to elevated beta-cell TXNIP levels.

The team subsequently went on to demonstrate that TXNIP does indeed induce beta-cell death by apoptosis: in mice models in which TXNIP had been genetically deleted, for example, the animals were completely protected against diabetes.

The next step was to identify a drug that could provide pharmacological inhibition of TXNIP.

Reduction of intracellular calcium inhibits the transcription and expression of TXNIP, the team discovered, so by using the calcium-channel blocker verapamil to do this, they were able to mimic the effects of genetically deleted TXNIP in mice and preserve the insulin-producing beta cells.

"Even after the animals had developed full-blown diabetes with high blood sugar levels, when we started treating them with verapamil, blood sugars normalized, and this was due to the reappearance and normalization of insulin-producing beta cells," Dr Shalev explained.

"With that, we had proof of principle that inhibition of TXNIP with verapamil could serve as a very attractive target to promote the body's own insulin-producing beta-cell mass."

Moving these findings from "bench-to-bedside," Dr Shalev said, the researchers are planning to enroll 52 patients between the ages of 19 and 45 in the study, ideally within 3 months of being diagnosed with type 1 diabetes.

They will be randomized to either verapamil or placebo and will be treated for 1 year while continuing with insulin-pump therapy and employing continuous glucose monitoring.

However, she noted, "We're not expecting any miracles with this study, since we will  be treating patients for only 1 year, and we know that for any intervention to create an environment conducive to beta-cell survival or even regeneration after such a large number of beta cells have died will take a long time."

The human study is being funded by JDRF, the largest charitable support of type 1 diabetes research. Dr Shalev reports she has no relevant financial relationships.

Mol Endocrinol. 2014:28:1211-1220. Article

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