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Title

Valproate inhibits glucose-stimulated insulin secretion in beta cells.

Authors

Yedulla, Nikhil R.; Naik, Akshata R.; Kokotovich, Keith M.; Yu, Wenxi; Greenberg, Miriam L.; Jena, Bhanu P.

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.

Subjects

VALPROIC acid; INSULIN; PANCREATIC beta cells; INOSITOL phosphatase; GLUCOSE metabolism

Publication

Histochemistry & Cell Biology, 2018, Vol 150, Issue 4, p395

ISSN

0948-6143

Publication type

Academic Journal

DOI

10.1007/s00418-018-1713-6

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