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David S. Paul,¹ Anne W. Harmon,¹ Vicenta Devesa,² David J. Thomas,³ and Miroslav Sty´blo^1,2

¹Department of Nutrition, and ²Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; ³Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA

Abstract
Background: Increased prevalences of diabetes mellitus have been reported among individuals chronically exposed to inorganic arsenic (iAs) . However, the mechanisms underlying the diabetogenic effects of iAs have not been characterized. We have previously shown that trivalent metabolites of iAs, arsenite (iAs^III) and methylarsonous acid (MAs^III) inhibit insulin-stimulated glucose uptake (ISGU) in 3T3-L1 adipocytes by suppressing the insulin-dependent phosphorylation of protein kinase B (PKB/Akt) .

Objectives: Our goal was to identify the molecular mechanisms responsible for the suppression of PKB/Akt phosphorylation by iAs^III and MAs^III.

Methods: The effects of iAs^III and MAs^III on components of the insulin-activated signal transduction pathway that regulate PKB/Akt phosphorylation were examined in 3T3-L1 adipocytes.

Results: Subtoxic concentrations of iAs^III or MAs^III had little or no effect on the activity of phosphatidylinositol 3-kinase (PI-3K) , which synthesizes phosphatidylinositol-3,4,5-triphosphate (PIP₃) , or on phosphorylation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) , a PIP₃ phosphatase. Neither iAs^III nor MAs^III interfered with the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1) located downstream from PI-3K. However, PDK-1 activity was inhibited by both iAs^III and MAs^III. Consistent with these findings, PDK-1-catalyzed phosphorylation of PKB/Akt(Thr308) and PKB/Akt activity were suppressed in exposed cells. In addition, PKB/Akt(Ser473) phosphorylation, which is catalyzed by a putative PDK-2, was also suppressed. Notably, expression of constitutively active PKB/Akt restored the normal ISGU pattern in adipocytes treated with either iAs^III or MAs^III.

Conclusions: These results suggest that inhibition of the PDK-1/PKB/Akt-mediated transduction step is the key mechanism for the inhibition of ISGU in adipocytes exposed to iAs^III or MAs^III, and possibly for impaired glucose tolerance associated with human exposures to iAs.

Key words: arsenic, diabetes, glucose uptake, PDK-1, PKB/Akt. Environ Health Perspect 115:734–742 (2007) . doi:10.1289/ehp.9867 available via http://dx.doi.org/ [Online 29 January 2007]

Address correspondence to M. Sty´blo, Department of Nutrition, CB# 7461, 2302 MHRC, The University of North Carolina, Chapel Hill, NC 27599-7461 USA. Telephone: (919) 966-5721. Fax: (919) 843-0776. E-mail: styblo@med.unc.edu

This work has been supported by a U.S. EPA Cooperative Agreement 282952201 and a Clinical Nutrition Research Center grant DK 56350 from the National Institutes of Health (NIH) . D.S.P. was supported in part by NIH Nutrition Training grant 5 T32 DK07686.

This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.