Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes.
Guanlan XuTiffany D GrimesTruman B GraysonJunqin ChenLance A ThielenHubert M TseTanja DudenbostelMatt KankeTai-Tu LinAthena A SchepmoesAdam C SwensenVladislav A PetyukFernando OvallePraveen SethupathyWei-Jun QianAnath ShalevPublished in: Nature communications (2022)
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.
Keyphrases
- type diabetes
- single cell
- placebo controlled
- phase iii
- double blind
- phase ii
- clinical trial
- endothelial cells
- study protocol
- cell death
- open label
- glycemic control
- mass spectrometry
- randomized controlled trial
- genome wide
- squamous cell carcinoma
- dna methylation
- cell therapy
- transcription factor
- drug induced
- metabolic syndrome
- amino acid
- induced pluripotent stem cells
- replacement therapy