Currently, there are no oral medications available for patients with type 1 diabetes. Insulin shots or pumps are the only ways to replace the life-threating loss of pancreatic beta cells caused by the autoimmune disease.
Now, a new study by researchers at the University of Alabama at Birmingham builds on and fortifies previous work demonstrating that an already approved high blood pressure drug may be the oral treatment many diabetics are looking for.
For more than 20 years, Anath Shalev, M.D., director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, studied the gene TXNIP, found in pancreatic islets. In 2014, Shalev’s lab discovered—accidentally—that verapamil completely reversed diabetes in animal models. Verapamil had been approved by the FDA in 1981 as a treatment for high blood pressure.
Continuing on this unexpected path, Shalev commenced a clinical study looking into verapamil for diabetes. In 2018, the study results showed that regular oral administration of verapamil enabled patients to produce higher levels of their own insulin, thus limiting their need for injected insulin.
Shalev’s most recent study, published in Nature Communications, extends that finding, providing crucial mechanistic and clinical insight.
The researchers analyzed blood serum samples from patients diagnosed with Type 1 diabetes within three months of diagnosis and again at one year of follow-up. In those that were treated with verapamil during the initial year, 53 proteins showed significantly altered relative abundance in response to the drug. The most significant serum protein altered by verapamil treatment was chromogranin A, or CHGA, which was downregulated with treatment.
At the onset of the study, healthy, non-diabetic volunteers had about 2x lower serum CHGA levels compared with Type 1 diabetic patients. However, according to the study results, after one year of oral treatment, verapamil-treated Type 1 diabetes patients recorded similar CHGA levels as those of healthy individuals.
Even more significantly, CHGA levels continued to drop in verapamil-treated subjects in the second year of the study. Conversely, the levels rose in Type 1 diabetes patients who discontinued verapamil during year two.
“Thus, serum CHGA seems to reflect changes in beta cell function in response to verapamil treatment or Type 1 diabetes progression and therefore may provide a longitudinal marker of treatment success or disease worsening,” said Shalev. “This would address a critical need, as the lack of a simple longitudinal marker has been a major challenge in the Type 1 diabetes field.”
Since previous literature has identified CHGA as an autoantigen that provokes immune T cells, Shalev and her team investigated whether verapamil had any effect on T cells. They found that not only were several proinflammatory markers of T follicular helper cells significantly elevated in patients with Type 1 diabetes, but that these changes were reversed by verapamil treatment.
“Now our results reveal for the first time that verapamil treatment may also affect the immune system and reverse these Type 1 diabetes-induced changes,” said Shalev. “This suggests that verapamil, and/or the Type 1 diabetes improvements achieved by it, can modulate some circulating proinflammatory cytokines and T helper cell subsets, which in turn may contribute to the overall beneficial effects observed clinically.”
The results of Shalev’s most recent study needs to be confirmed by a larger clinical study, which is currently ongoing in Europe. Still, Shalev says, the results are exceedingly promising.
“In humans with Type 1 diabetes, even a small amount of preserved endogenous insulin production has been shown to be associated with improved outcomes and could help improve quality of life and lower the high costs associated with insulin use,” she said. “The fact that these beneficial verapamil effects seemed to persist for two years, whereas discontinuation of verapamil led to disease progression, provides some additional support for its potential usefulness for long-term treatment.”