Study Suggests Blood-Pressure Drug May Slow Diabetes Progression
A common high-blood-pressure medication appears to reverse the diabetes-related death of pancreatic beta cells, according to a University of Alabama at Birmingham (UAB) study published in Diabetes.
The authors argue that the findings—while in human pancreatic islets and diabetic mice—could have clinical implications as physicians consider that calcium channel blockers may address two major, related diseases. They also found evidence in past clinical trials that the study drug verapamil may slow diabetes.
Beta cells secrete insulin to control blood sugar levels, but begin to die as patients develop type 1 or type 2 diabetes. No one suspected that calcium channel blockers might reverse beta cell death because the studies that led to their FDA approval measured their effect on heart attacks, not blood sugar. UAB researchers were surprised when hints of verapamil’s effect were discovered amid their effort to design a drug to shut down a protein called TXNIP.
The team had published several papers over 10 years that describe the way high blood sugar uniquely turns on the gene for TXNIP, and how excessive TXNIP-signaling in diabetes signals cells to self-destruct. Recent studies also have suggested that lowering TXNIP levels in the heart lessens the damage caused by a heart attack.
“We long have felt that finding an oral medication that inhibits beta cell TXNIP expression would represent a major breakthrough, and now we have the first study showing that a drug already proven safe in years of clinical practice may halt the development of diabetes,” says Anath Shalev, MD, director of the UAB Comprehensive Diabetes Center and senior author of the paper. “Our results are encouraging because patients with diabetes suffer from beta cell death as part of their disease, there has been no treatment targeting this problem and TXNIP-inhibition promises to reverse it.”
Based on its findings, the UAB team has redoubled its original effort to design a new class of TXNIP-inhibitors. In partnership with the Southern Research Institute and the Alabama Drug Discovery Alliance, they are now screening a library of 300,000 molecules, a search they hope will yield drug candidates that reverse beta cell death without affecting blood pressure.
In cell studies, the team found that verapamil reduced TXNIP gene expression 50%. In diabetic mice, verapamil treatment maintained normal glucose level, while glucose spiked in control mice. This was accompanied by an 80% reduction in TXNIP levels in isolated islets of verapamil-treated animals.
Using molecular biology techniques, researchers were able to watch as expression of TXNIP, or thioredoxin-interacting protein, rose in beta cells to abnormal levels as mice became diabetic and then fell again as they received verapamil.
The team also found that treatment only reduced TXNIP gene expression when high blood sugar had driven it to abnormal levels, making the pathway “extremely attractive” as a target for drugs, Shalev says. Future treatments conceivably could return TXNIP levels to normal in diabetic patients, but leave in place the basic level of TXNIP-signaling that cells rely on to regulate life processes. The results also suggest the drug is able to slow diabetes in mice with longstanding disease and is more effective when given early.
In addition to protecting insulin-producing cells, experiments also showed that verapamil countered insulin-resistance that makes the hormone less able to lower blood-sugar levels in diabetic patients. Theory has it that lowering TXNIP levels counters this by increasing glucose uptake in the tissues targeted by insulin (eg, muscle and fat), a phenomenon observed in mice lacking the TXNIP gene.
Source: University of Alabama at Birmingham