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

Author

Listed:
  • Guanlan Xu

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Tiffany D. Grimes

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Truman B. Grayson

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Junqin Chen

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Lance A. Thielen

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Hubert M. Tse

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Peng Li

    (University of Alabama at Birmingham
    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
    University of Alabama at Birmingham)

  • Praveen Sethupathy

    (Cornell University)

  • Wei-Jun Qian

    (Pacific Northwest National Laboratory)

  • Anath Shalev

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

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.

Suggested Citation

  • 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 & , 2022. "Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28826-3
    DOI: 10.1038/s41467-022-28826-3
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    References listed on IDEAS

    as
    1. Sangtae Kim & Pavel A. Pevzner, 2014. "MS-GF+ makes progress towards a universal database search tool for proteomics," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    2. Maikel L. Colli & Mireia Ramos-Rodríguez & Ernesto S. Nakayasu & Maria I. Alvelos & Miguel Lopes & Jessica L. E. Hill & Jean-Valery Turatsinze & Alexandra Coomans de Brachène & Mark A. Russell & Helen, 2020. "An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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