Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress

• Published in: Toxicology (Amsterdam) Vol. 263; no. 2; pp. 75 - 83
• Main Authors: García-Montalvo, Eliud A, Reyes-Pérez, Hugo, Del Razo, Luz M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ireland Ltd 19.09.2009; Elsevier
• Subjects: Animals; Benzidines - metabolism; Biological and medical sciences; Blood Glucose - analysis; Blood Glucose - metabolism; Cell Survival - drug effects; Cells, Cultured; Chromogenic Compounds - metabolism; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Emergency; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting; Fluorides - pharmacology; Fluorides - urine; Gene Expression - drug effects; Glibenclamide; Glucose - pharmacology; Glucose Tolerance Test; Hypoglycemic Agents - metabolism; Insulin - metabolism; Insulin expression; Insulin secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - secretion; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mitochondrial membrane potential; Oxidative Stress - drug effects; Pancreatic β-cells; RNA, Messenger - metabolism; Sensitivity and Specificity; Sodium fluoride; Time Factors; Toxicology; Insulin expression; Sodium fluoride; Pancreatic β-cells; Glibenclamide; Insulin secretion; Mitochondrial membrane potential; Endocrinopathy; Oxidative stress; Pancreatic hormone; Secretion; Toxicity; Langerhans islet; Electrophysiology; Exposure; Insulin; Hypoglycemic agent; Mitochondria; Sulfonamides; Sulfonylureas; β Cell; Membrane potential; Impaired glucose tolerance; Endocrine pancreas
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2009.06.008

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 β-cells (βTC-6) exposed to F− . Mice received 45 mg l−1 F− , as NaF, via drinking water, and cells were exposed for 12 h 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 16.6 mM, respectively). Mice showed marginal hyperglycemia an impaired glucose tolerance after 4 weeks of F− exposure, while β-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 β-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 (O2− ), showed significantly decreased SOD activity, in a dose-dependent manner. This was accompanied by an increase in the generation of O2− , and decreased mitochondrial membrane potential in F− exposed cells. Insulin secretion was lower in β-cells exposed to F− , even in the presence of glibenclamide, the ATP-sensitive K+ (KATP ) channel blocker, suggesting down-regulation of the KATP channel in the cell. Exposure to high levels of F− in drinking water may decrease insulin mRNA and its secretion from β-cells, and might therefore affect the OG T T.