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MOLECULAR MECHANISMS OF DIABETOGENIC EFFECTS OF ARSENIC: INHIBITION OF INSULIN SIGNALING BY ARSENITE AND METHYLARSONOUS ACID
Citation:
PAUL, D. S., A. HARMON, V. DEVESA I PEREZ, D. J. THOMAS, AND M. STYBLO. MOLECULAR MECHANISMS OF DIABETOGENIC EFFECTS OF ARSENIC: INHIBITION OF INSULIN SIGNALING BY ARSENITE AND METHYLARSONOUS ACID. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 115(5):734-42, (2007).
Impact/Purpose:
to better understand the molecular mechanisms of diabetes
Description:
Increased prevalence of diabetes mellitus has been reported among individuals chronically exposed to inorganic arsenic (iAs). However, mechanisms underlying the diabetogenic effects of iAs have not been characterized. We have shown that trivalent metabolites of iAs inhibit insulin-stimulated glucose uptake in 3T3-L1 adipocytes by a mechanism that involves suppression of insulin-dependent phosphorylation of protein kinase B (PKB/Akt). The present study examined the effects of two of these metabolites, arsenite (iAsIII) and methylarsonous acid (MAsIII), on components of the insulin-activated signal transduction pathway that regulate PKB/Akt phosphorylation. Exposures to subtoxic concentrations of iAsIII or MAsIII had no effect on the activity of phosphatidylinositol 3-kinase (PI-3K), which synthesizes phosphatidylinositol-3, 4, 5-triphosphate (PIP3) in response to insulin or on phosphorylation of PTEN, a PIP3 phosphatase. Neither iAsIII nor MAsIII interfered with phopshorylation of 3-phosphoinositide-dependent protein kinase-1 (PDK-1) located downstream from PI-3K. However, PDK-1 activity was inhibited by both iAsIII and MAsIII. 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(Ser437) phosphorylation, which is catalyzed by a putative PDK-2, was also suppressed. MAsIII was considerably more potent than iAsIII as an inhibitor of PDK-1 activity and PKB/Akt phosphorylation. Notably, expression of constitutively active PKB/Akt restored normal glucose uptake pattern in insulin-stimulated adipocytes treated with either iAsIII or MAsIII. These results suggest that inhibition of the PDK-1/PKB/Akt-mediated transduction step is the key mechanism for the inhibition of glucose uptake in adipocytes exposed to subtoxic concentrations of iAsIII or MAsIII, and possibly for impaired glucose tolerance associated with human exposures to iAs.