Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes

• Published in: Toxicology and applied pharmacology Vol. 198; no. 3; pp. 424 - 433
• Main Authors: Walton, Felecia S, Harmon, Anne W, Paul, David S, Drobná, Zuzana, Patel, Yashomati M, Styblo, Miroslav
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-08-2004; Elsevier
• Subjects: Akt; Animals; Arsenic; Arsenicals - adverse effects; Arsenicals - metabolism; Arsenicals - pharmacology; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Chemical and industrial products toxicology. Toxic occupational diseases; Diabetes; Diabetes Mellitus, Type 2 - chemically induced; Glucose - metabolism; Glucose uptake; GLUT4; Insulin; Insulin - pharmacology; Medical sciences; Metals and various inorganic compounds; Methylation; Mice; PKB; Toxicology; Glucose uptake; Arsenic; PKB; Diabetes; Akt; Methylation; GLUT4; Insulin; Endocrinopathy; Protein kinase B; Diabetes mellitus; Glucose; Uptake; Inhibitor; Inhibition
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2003.10.026

Chronic exposures to inorganic arsenic (iAs) have been associated with increased incidence of noninsulin (type-2)-dependent diabetes mellitus. Although mechanisms by which iAs induces diabetes have not been identified, the clinical symptoms of the disease indicate that iAs or its metabolites interfere with insulin-stimulated signal transduction pathway or with critical steps in glucose metabolism. We have examined effects of iAs and methylated arsenicals that contain trivalent or pentavalent arsenic on glucose uptake by 3T3-L1 adipocytes. Treatment with inorganic and methylated pentavalent arsenicals (up to 1 mM) had little or no effect on either basal or insulin-stimulated glucose uptake. In contrast, trivalent arsenicals, arsenite (iAs
III), methylarsine oxide (MAs
IIIO), and iododimethylarsine (DMAs
IIIO) inhibited insulin-stimulated glucose uptake in a concentration-dependent manner. Subtoxic concentrations of iAs
III (20 μM), MAs
IIIO (1 μM), or DMAs
IIII (2 μM) decreased insulin-stimulated glucose uptake by 35–45%. Basal glucose uptake was significantly inhibited only by cytotoxic concentrations of iAs
III or MAs
IIIO. Examination of the components of the insulin-stimulated signal transduction pathway showed that all trivalent arsenicals suppressed expression and possibly phosphorylation of protein kinase B (PKB/Akt). The concentration of an insulin-responsive glucose transporter (GLUT4) was significantly lower in the membrane region of 3T3-L1 adipocytes treated with trivalent arsenicals as compared with untreated cells. These results suggest that trivalent arsenicals inhibit insulin-stimulated glucose uptake by interfering with the PKB/Akt-dependent mobilization of GLUT4 transporters in adipocytes. This mechanism may be, in part, responsible for the development of type-2 diabetes in individuals chronically exposed to iAs.