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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
Nature communications, 03/2022, Letnik: 13, Številka: 1Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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