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Multiple animal models of inorganic arsenic (iAs, as As<jats:sup>3+<\/jats:sup>) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic \u03b2-cell dysfunction. To define the mechanisms responsible for this \u03b2-cell defect, the MIN6-K8 mouse \u03b2-cell line was exposed to environmentally relevant doses of iAs. Exposure to 0.1\u20131 \u00b5M iAs for 3 days significantly decreased glucose-induced insulin secretion (GIIS). Serotonin and its precursor, 5-hydroxytryptophan (5-HTP), were both decreased. Supplementation with 5-HTP, which loads the system with bioavailable 5-HTP and serotonin, rescued GIIS, suggesting that recovery of this pathway was sufficient to restore function. Exposure to iAs was accompanied by an increase in mRNA expression of UDP-glucuronosyltransferase 1 family, polypeptide a6a ( Ugt1a6a), a phase-II detoxification enzyme that facilitates the disposal of cyclic amines, including serotonin, via glucuronidation. Elevated Ugt1a6a and UGT1A6 expression levels were observed in mouse and human islets, respectively, following 3 days of iAs exposure. Consistent with this finding, the enzymatic rate of serotonin glucuronidation was increased in iAs-exposed cells. Knockdown by siRNA of Ugt1a6a during iAs exposure restored GIIS in MIN6-K8 cells. This effect was prevented by blockade of serotonin biosynthesis, suggesting that the observed iAs-induced increase in Ugt1a6a affects GIIS by targeting serotonin or serotonin-related metabolites. Although it is not yet clear exactly which element(s) of the serotonin pathway is\/are most responsible for iAs-induced GIIS dysfunction, this study provides evidence that UGT1A6A, acting on the serotonin pathway, regulates GIIS under both normal and pathological conditions. <\/jats:p>","DOI":"10.1152\/ajpendo.00302.2018","type":"journal-article","created":{"date-parts":[[2018,12,18]],"date-time":"2018-12-18T15:25:16Z","timestamp":1545146716000},"page":"E464-E474","source":"Crossref","is-referenced-by-count":22,"title":["Arsenic modifies serotonin metabolism through glucuronidation in pancreatic \u03b2-cells"],"prefix":"10.1152","volume":"316","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7662-9946","authenticated-orcid":false,"given":"Christopher M.","family":"Carmean","sequence":"first","affiliation":[{"name":"Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 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