Tackling diabetes with an oral drug that blocks a glucose-induced gene

Back in 2014, researchers at the University of Alabama at Birmingham (UAB) launched a human trial of verapamil, a blood pressure medication, in patients with diabetes, because they had preclinical evidence that the drug could lower levels of TXNIP, a protein that can destroy insulin-producing beta cells in the pancreas. That study turned in mixed results, but the same team of UAB researchers continued pursuing the idea that targeting the TXNIP gene could be a viable strategy to fight both Type 1 and Type 2 diabetes.

Now, the researcher say they have found a small-molecule drug that is showing promising properties in mouse models of diabetes. The drug candidate, dubbed SRI-37330, normalized blood glucose in rodent models of severe Type 2 diabetes and prevented mice from developing a form of Type 1 diabetes, the researchers reported in the journal Cell Metabolism. The drug outperformed the popular diabetes drugs metformin and Jardiance at controlling blood sugar, they said.

The team, led by Anath Shalev, M.D., professor of medicine at UAB, screened 300,000 compounds in search of one that could act on the two major hormones that malfunction in diabetes—insulin and glucagon. They found that SRI-37330 directly targets the pancreatic islets that produce insulin and glucagon.

Shalev and her colleagues had previously discovered that levels of the TXNIP protein were elevated in both human islets and mouse models of diabetes. When they deleted the gene in the mice, the animals were protected from the disease. They also discovered that TXNIP had a negative impact on the functioning of islets and on their survival.

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The blood pressure drug verapamil is a calcium channel blocker that indirectly inhibits TXNIP, so Shalev’s team was optimistic about the 2014 trial of the drug, in which they tested it in adults with newly diagnosed Type 1 diabetes. Verapamil did seem to preserve beta cell function and reduce the amount of insulin patients needed, they reported. But it didn’t affect levels of glucagon, which, when elevated, can interfere with insulin functioning.

The UAB researchers observed that SRI-37330 lowered blood glucose by reducing the amount of glucagon in the blood in addition to inhibiting glucose production in the liver, they reported. The drug did not cause dangerously low blood glucose, known as hypoglycemia, in the mice, and it did not cause toxic side effects, even at doses that were higher than what was needed to achieve a therapeutic effect, they said.

The mice were obese when they were given SRI-37330 in their drinking water. The UAB researchers were surprised to discover that in addition to normalizing blood glucose, the drug seemed to reduce levels of fat in the liver, suggesting it “might also be beneficial in the context of non-alcoholic fatty liver disease, a complication frequently associated with diabetes and/or obesity,” Shalev said in a statement.

In the publication, the scientists noted that more research needs to be done to define the precise molecular targeting of SRI-37330. But the fact that twice-daily dosing of the drug by mouth was effective in the mice after the onset of disease “raises the possibility that SRI-37330 may ultimately lead to a much needed oral drug that could also be used for type 1 diabetes,” they suggested.