Year: 2018
Type: article
Abstract: ) 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.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Diabetes Association, Honjo International Scholarship Foundation, National Institutes of Health, U.S. Public Health Service, MSD K.K., Japan Society for the Promotion of Science, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences
Awards: Elucidation of pancreatic beta-cell function by metabolomics and its clinical application, The physiological and pathophysiological roles of glutamate signaling in pancreatic beta-cell, G4997024190, The role of Epac2A/Rap1 signaling in the protection of pancreatic beta-cell, Selenoproteins in Arsenic-Induced Metabolic Dysfunction, 糖尿病のインクレチン応答性インスリン分泌不全の分子機構解明とその治療戦略の確立, Elucidation of genetic factors and mechanisms involved in the development and progression of type 2 diabetes using a novel rat model of the disease, Diabetes Research and Training Center, Establishment of quantification method of glucagon-related peptides and elucidation of pathophysiological role of the peptides, G9000001850, G9000337377, ChicAgo Center for Health and EnvironmenT (CACHET), Diabetes Research and Training Center
OpenAlex ID: W2903878345