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

Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen, Hubert M. Tse, Peng Li, Matt Kanke, Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk, Fernando Ovalle, Praveen Sethupathy, Wei-Jun Qian and Anath Shalev ()
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Guanlan Xu: University of Alabama at Birmingham
Tiffany D. Grimes: University of Alabama at Birmingham
Truman B. Grayson: University of Alabama at Birmingham
Junqin Chen: University of Alabama at Birmingham
Lance A. Thielen: University of Alabama at Birmingham
Hubert M. Tse: University of Alabama at Birmingham
Peng Li: University of Alabama at Birmingham
Matt Kanke: Cornell University
Tai-Tu Lin: Pacific Northwest National Laboratory
Athena A. Schepmoes: Pacific Northwest National Laboratory
Adam C. Swensen: Pacific Northwest National Laboratory
Vladislav A. Petyuk: Pacific Northwest National Laboratory
Fernando Ovalle: University of Alabama at Birmingham
Praveen Sethupathy: Cornell University
Wei-Jun Qian: Pacific Northwest National Laboratory
Anath Shalev: University of Alabama at Birmingham

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28826-3

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