Introduction and Objective: We have discovered that verapamil inhibits pancreatic islet expression of beta cell toxic thioredoxin-interacting protein (TXNIP) and preserves beta cell function in mice and in subjects with T1D and these clinical findings have been independently validated. However, as a calcium channel blocker, verapamil has many additional effects. We therefore aimed to explore the genes/proteins regulated by verapamil in the context of diabetes.Methods: We performed proteomics on serum samples of T1D subjects treated with placebo or verapamil. We also conducted transcriptomics on human islets treated with or without verapamil. Common genes/proteins significantly downregulated by verapamil in both omics were selected and analyzed in islets in the context of diabetes and inflammation. In addition, we analyzed the effect of verapamil on these genes in islets and islet endothelial cells.Results: We found five common proteins/genes (VCAM1, SPINK1, SYCN, PI16 and CD14) significantly decreased by verapamil in both omics. Besides its important role in immune cell transmigration and in diabetes, we chose VCAM1 for further study because SPINK1 is exclusively expressed in exocrine cells while the other genes are very lowly expressed in islets. We found that the serum levels of VCAM1 were significantly decreased in T1D subjects after 1 year of verapamil but not placebo treatment. In addition, VCAM1 expression was increased in islets of diabetic NOD mice, T2D subjects and in human islets treated with T1D-associated cytokines. Furthermore, we demonstrated that the expression of VCAM1 and two other adhesion molecules (PECAM1 and ESAM) was significantly decreased by verapamil in human islets and mouse islet endothelial cells.Conclusion: VCAM1 is significantly increased in islets in the context of diabetes and inflammation, which may play an important role in T cell infiltration into islets in T1D. The inhibition of VCAM1 and other vascular adhesion molecules by verapamil may contribute to the potential protective effects of this drug against islet inflammation.
G. Xu: None. J. Chen: None. B. Lu: None. A. Shalev: Other Relationship; TIXiMED, Inc.
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