title: Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress.
abstract: Chronic exposure to high fluoride (F(-)) may lead to local tissue disturbances, known as fluorosis. F(-) is an oxidising agent and a well-known reversible enzymatic inhibitor that interferes with the enzyme activity of at least 80 proteins. The goals of the current study were to evaluate whether F(-) exposure affected the oral glucose tolerance test (OGTT) in C57BL6 mice; and to determine the mechanisms at work in glucose homeostasis at the cellular level, in mouse pancreatic beta-cells (betaTC-6) exposed to F(-). Mice received 45 mgl(-1) F(-), as NaF, via drinking water, and cells were exposed for 12h to NaF (equivalent to 0, 0.007, 0.045, 0.180, 1.35 or 2.26 mM F(-)) at a basal or stimulatory glucose concentration (2.8 or 16.6mM, respectively). Mice showed marginal hyperglycemia an impaired glucose tolerance after 4 weeks of F(-) exposure, while beta-cells exposed to 1.35 and 2.26 mM F(-) had significantly lower insulin mRNA expression and subsequent secretion in the presence of the stimulatory glucose concentration. Western blot analyses did not show any alteration in the levels of glucose transporter-2 protein beta-cells on exposure to F(-)in vitro. However, oxidative stress evaluated by the functional activity of superoxide dismutase (SOD) and generation of the superoxide anion (O(2)(-)), showed significantly decreased SOD activity, in a dose-dependent manner. This was accompanied by an increase in the generation of O(2)(-), and decreased mitochondrial membrane potential in F(-) exposed cells. Insulin secretion was lower in beta-cells exposed to F(-), even in the presence of glibenclamide, the ATP-sensitive K(+) (K(ATP)) channel blocker, suggesting down-regulation of the K(ATP) channel in the cell. Exposure to high levels of F(-) in drinking water may decrease insulin mRNA and its secretion from beta-cells, and might therefore affect the OGTT.
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Av. IPN 2508, San Pedro Zacatenco, México, D.F. 07360, Mexico.
authors.forename: Eliud A
authors.initials: EA
authors.lastname: García-Montalvo
authors.forename: Hugo
authors.initials: H
authors.lastname: Reyes-Pérez
authors.forename: Luz M
authors.initials: LM
authors.lastname: Del Razo
mesh_terms: D000818:Animals; D001560:Benzidines / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002863:Chromogenic Compounds / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting; D005459:Fluorides / Q000494:pharmacology* / Q000652:urine; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D001560:Benzidines; D001786:Blood Glucose; D002863:Chromogenic Compounds; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; C021758:3,3',5,5'-tetramethylbenzidine; D005947:Glucose; D005459:Fluorides