PNNL

Abstract

Currently, no oral medications are available for individuals suffering from type 1 diabetes (T1D). Our randomized placebo-controlled phase 2 trial recently revealed that oral verapamil has shortterm beneficial effects in subjects with new-onset type 1 diabetes (T1D) 1. However, what exact biological changes verapamil elicits in humans with T1D, how long they may last, and how to best monitor any associated therapeutic success has remained elusive. We therefore now conducted extended analyses of the effects of continuous verapamil use over a 2-year period, performed unbiased proteomics analysis of serum samples and assessed changes in proinflammatory T-cell markers in subjects receiving verapamil or just standard insulin therapy. In addition, we determined the verapamil-induced changes in human islets using RNA sequencing. Our present results reveal that verapamil regulates the thioredoxin system and promotes an anti-oxidative and anti-apoptotic gene expression profile in human islets, reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cells and interleukin-21 and normalizes serum levels of chromogranin A (CHGA), a recently identified T1D autoantigen 2,3. In fact, proteomics identified CHGA as the top serum protein altered by verapamil and as a potential therapeutic marker. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.