Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes

• Published in: Nature communications Vol. 13; no. 1; pp. 1159 - 9
• Main Authors: Xu, Guanlan, Grimes, Tiffany D., Grayson, Truman B., Chen, Junqin, Thielen, Lance A., Tse, Hubert M., Li, Peng, Kanke, Matt, Lin, Tai-Tu, Schepmoes, Athena A., Swensen, Adam C., Petyuk, Vladislav A., Ovalle, Fernando, Sethupathy, Praveen, Qian, Wei-Jun, Shalev, Anath
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/39; 38/88; 38/91; 60 APPLIED LIFE SCIENCES; 631/443/319/1642/137/1418; 692/163/2743/137/1418; 82/58; Apoptosis; Beta cells; Biomarkers; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1; Gene expression; Gene sequencing; Humanities and Social Sciences; Humans; Immunologic Factors - therapeutic use; Immunomodulation; Immunotherapy; Inflammation; Insulin; multidisciplinary; Proteomics; Science; Science (multidisciplinary); Thioredoxin; Type 1 diabetes; Verapamil; Verapamil - pharmacology; Verapamil - therapeutic use
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28826-3

Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. 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. Oral verapamil lowers inflammatory markers and daily insulin needs in subjects with type 1 diabetes and helps preserve pancreatic beta cell function for at least two years. In this context, serum chromogranin A provides a promising therapy marker.