Abstract
Valproate (VPA), an FDA approved anti-epileptic drug with a half-life of 12–18 h in humans, has been shown to perturb the vacuolar proton pump (vH+-ATPase) function in yeasts by inhibiting myo-inositol phosphate synthase, the first and rate-limiting enzyme in inositol biosynthesis, thereby resulting in inositol depletion. vH+-ATPase transfers protons (H+) across cell membranes, which help maintain pH gradients within cells necessary for various cellular functions including secretion. This proton pump has a membrane (V0) and a soluble cytosolic (V1) domain, with C-subunit associated with V1. In secretory cells such as neurons and insulin-secreting beta cells, vH+-ATPase acidifies vesicles essential for secretion. In this study, we demonstrate that exposure of insulin-secreting Min6 cells to a clinical dose of VPA results in inositol depletion and loss of co-localization of subunit C of vH+-ATPase with insulin-secreting granules. Consequently, a reduction of glucose-stimulated insulin secretion is observed following VPA exposure. These results merit caution and the reassessment of the clinical use of VPA.
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Acknowledgements
Work presented in this article was supported in part by the National Science Foundation Grant CBET1066661 (BPJ); the WSU Interdisciplinary Biomedical Systems Fellowship (ARN); and R01 GM125082-05A1 from the National Institutes of Health (to M.L.G.). All authors critically analyzed results and proof read the manuscript.
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Yedulla, N.R., Naik, A.R., Kokotovich, K.M. et al. Valproate inhibits glucose-stimulated insulin secretion in beta cells. Histochem Cell Biol 150, 395–401 (2018). https://doi.org/10.1007/s00418-018-1713-6
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DOI: https://doi.org/10.1007/s00418-018-1713-6