Valproate inhibits glucose-stimulated insulin secretion in beta cells
| Autor: | Akshata R. Naik, Keith M. Kokotovich, Nikhil R Yedulla, Bhanu P. Jena, Wenxi Yu, Miriam L. Greenberg |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Histology Protein subunit Cell Article Mice 03 medical and health sciences chemistry.chemical_compound Insulin-Secreting Cells Insulin Secretion Tumor Cells Cultured medicine Animals Insulin Secretion Inositol Molecular Biology chemistry.chemical_classification ATP synthase biology Valproic Acid Vesicle Cell Biology Cell biology Medical Laboratory Technology Cytosol Glucose 030104 developmental biology Enzyme medicine.anatomical_structure chemistry biology.protein |
| Zdroj: | Histochemistry and Cell Biology. 150:395-401 |
| ISSN: | 1432-119X 0948-6143 |
| Popis: | Valproate (VPA), an FDA approved anti-epileptic drug with a half-life of 12–18h 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 helps maintain pH gradients within cells necessary for various cellular functions including secretion. This proton pump has a membrane (V(0)) and a soluble cytosolic (V(1)) domain, with C-subunit associated with V(1). 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. |
| Databáze: | OpenAIRE |
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