Format

Send to

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

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

Author information

1
Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine , Kobe , Japan.
2
Kansai Electric Power Medical Research Institute , Kobe , Japan.
3
Department of Pathology, College of Medicine, University of Illinois at Chicago , Chicago, Illinois.
4
Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago , Chicago, Illinois.
5
Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Sciences , Kobe , Japan.
6
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago , Chicago, Illinois.
7
Department of Pharmaceutics, Faculty of Pharmacy, Meijo University , Nagoya , Japan.

Abstract

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

PMID:
30562058
PMCID:
PMC6459295
[Available on 2020-03-01]
DOI:
10.1152/ajpendo.00302.2018

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center