medwireNews: Researchers report that the antihypertensive medication verapamil preserves beta-cell function and reduces insulin needs in adults with type 1 diabetes during up to 2 years of treatment.
Moreover, Anath Shalev (University of Alabama at Birmingham, USA) and study co-authors have identified a potential biomarker of treatment response, which may also reflect the mechanism of verapamil benefit.
The publication in Nature Communications builds on the team’s previous findings that people with type 1 diabetes given the calcium-channel blocker verapamil for a year had better beta-cell function, fewer hypoglycemic events, and needed less insulin than those given placebo.
After the conclusion of the 1-year phase 2 randomized trial, five participants continued taking verapamil and, over the next year, their C-peptide area under the curve (AUC) remained stable.
A further four participants discontinued verapamil and had a C-peptide AUC reduction of approximately 45% over the next year. C-peptide also continued to decline in the six participants taking placebo, by around 30% over the second year.
Exogenous insulin requirement also remained stable in the verapamil users during the second year, at around 0.25 U/kg per day, whereas this increased in people who discontinued, to nearly 0.5 U/kg per day, which was close to the 2-year insulin requirement in the placebo group.
“[I]n humans with [type 1 diabetes] even a small amount of preserved endogenous insulin production as opposed to higher exogenous insulin requirements has been shown to be associated with improved outcome and could help improve quality of life and lower the high costs associated with insulin use,” observe Shalev and colleagues.
In a global proteomics analysis to assess potential mechanisms of verapamil benefit, the team identified 53 serum proteins whose levels changed in response to verapamil treatment.
Chief of these was the type 1 diabetes autoantigen chromogranin A (CHGA). At baseline, serum levels of this protein were elevated in the participants with type 1 diabetes compared with levels in nine healthy controls. During the first year of the study, CHGA remained stable or increased in people with type 1 diabetes taking placebo, whereas they decreased in all those taking verapamil, to a level similar to that in the healthy volunteers.
Moreover, during year 2, CHGA levels in people who discontinued verapamil rose until they were on a par with those seen in the placebo group.
“Intriguingly, CHGA has also been identified as an autoantigen in [type 1 diabetes] and one of its peptide fragments has been reported to be recognized as an epitope by diabetogenic T-cells,” say the researchers.
Together with the current findings, “this raised the question of whether verapamil might also have any effects on T-cells,” they add.
The team found increased expression of CXCR5 and the associated interleukin (IL)-21 in the peripheral blood mononuclear cells of people with type 1 diabetes at baseline versus healthy controls, indicating increased levels of pro-inflammatory T-follicular helper (Tfh) cells. Furthermore, levels of Tfh cells and IL-21 fell in people given verapamil.
The researchers cite recent research suggesting that Tfh cells and IL-21 play “an important role” in the autoimmunity underlying type 1 diabetes.
“In fact, this may help explain why verapamil treatment was so successful even in the absence of any additional bona fide immunomodulatory intervention,” they say.
Shalev and team also found evidence for direct effects of verapamil on the pancreatic islets, with a total of 907 genes upregulated and 619 downregulated in samples from three treated participants relative to three who were untreated.
Analysis of the affected genes indicated that “verapamil regulates the thioredoxin system and promotes an antioxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets,” they say.
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