Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

Am J Physiol Endocrinol Metab. 2019 Mar 1;316(3):E464-E474. doi: 10.1152/ajpendo.00302.2018. Epub 2018 Dec 18.


In arsenic-endemic regions of the world, arsenic exposure correlates with diabetes mellitus. Multiple animal models of inorganic arsenic (iAs, as As3+) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic β-cell dysfunction. To define the mechanisms responsible for this β-cell defect, the MIN6-K8 mouse β-cell line was exposed to environmentally relevant doses of iAs. Exposure to 0.1-1 µM 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.

Keywords: arsenic; diabetes; glucuronidation; insulin secretion; serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Hydroxytryptophan / drug effects*
  • 5-Hydroxytryptophan / metabolism
  • Adult
  • Animals
  • Arsenic / pharmacology*
  • Cell Line
  • Diabetes Mellitus / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Glucose / metabolism
  • Glucuronosyltransferase / drug effects*
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Humans
  • Insulin Secretion / drug effects*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mitochondria
  • Oxygen Consumption
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Serotonin / metabolism*


  • RNA, Messenger
  • Serotonin
  • 5-Hydroxytryptophan
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase 1a6a, mouse
  • Glucose
  • Arsenic