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

Walton, Felecia S.; Harmon, Anne W.; Paul, David S.; Drobná, Zuzana; Patel, Yashomati M.; Stýblo, Miroslav

doi:10.1016/j.taap.2003.10.026

Cited by 162 publications

(125 citation statements)

References 65 publications

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“…We have previously shown that trivalent arsenicals, the metabolites of iAs, are potent inhibitors of insulin-stimulated glucose uptake in cultured adipocytes (Paul et al, submitted;Walton et al, 2004). Subtoxic concentrations of iAs III and MAs III inhibited the insulin-dependent phosphorylation of PKB/Akt by PDK-1 and p-PKB/Akt-dependent translocation of GLUT4 to the plasma membrane.…”

Section: Discussionmentioning

confidence: 93%

“…Here, dose-dependent decreases in ISGU were observed in 3T3-L1 adipocytes exposed for 4 or 24 h to subtoxic concentrations of iAs III , or the methylated metabolites of iAs, methylarsonite (MAs III ) and dimethylarsinite (DMAs III ) (Walton et al, 2004). We have recently shown that two of these arsenicals, iAs III or MAs III , inhibit the activity of 3-phosphoinositide dependent kinase 1 (PDK-1) and the subsequent PDK-1-catalyzed phosphorylation of PKB/Akt (Paul et al, submitted).…”

Section: Laboratory Studies Of the Effects Of As On Glucose Metabolismmentioning

confidence: 88%

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Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

Paul

Hernández-Zavala

Walton

et al. 2007

Toxicology and Applied Pharmacology

125

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Previous epidemiologic studies found increased prevalences of type 2 diabetes mellitus in populations exposed to high levels of inorganic arsenic (iAs) in drinking water. Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research has shown that exposures to iAs can produce effects that are consistent with type 2 diabetes. The current paper reviews the results of laboratory studies that examined the effects of iAs on glucose metabolism and describes new experiments in which the diabetogenic effects of iAs exposure were reproduced in a mouse model. Here, weanling male C57BL/6 mice drank deionized water with or without the addition of arsenite (25 or 50 ppm As) for 8 weeks. Intraperitoneal glucose tolerance tests revealed impaired glucose tolerance in mice exposed to 50 ppm As, but not to 25 ppm As. Exposure to 25 and 50 ppm As in drinking-water resulted in proportional increases in the concentration of iAs and its metabolites in the liver and in organs targeted by type 2 diabetes, including pancreas, skeletal muscle and adipose tissue. Dimethylarsenic was the predominant form of As in the tissues of mice in both 25 and 50 ppm groups. Notably, the average concentration of total speciated arsenic in livers from mice in the 50 ppm group was comparable to the highest concentration of total arsenic reported in the livers of Bangladeshi residents who had consumed water with an order of magnitude lower level of iAs. These data suggest that mice are less susceptible than humans to the diabetogenic effects of chronic exposure to iAs due to a more efficient clearance of iAs or its metabolites from target tissues.

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Section: Discussionmentioning

confidence: 93%

Section: Laboratory Studies Of the Effects Of As On Glucose Metabolismmentioning

confidence: 88%

Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

Paul

Hernández-Zavala

Walton

et al. 2007

Toxicology and Applied Pharmacology

125

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“…Similar differences between the uptake and/or retention of iAs III and methylated trivalent arsenicals have been found in primary rat hepatocytes (Styblo et al, 2000) and differentiated 3T3-L1 adipocytes (Devesa et al, unpublished results). Notably, MAs III and DMAs III are significantly more cytotoxic than iAs III for all these and other cell types (Styblo et al, 2000Walton et al, 2004). Thus, greater cellular uptakes and retention of MAs III and DMAs III are likely to contribute to the greater toxicities of methylated trivalent arsenicals in cell culture systems.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

Drobná

Waters

Devesa

et al. 2005

Toxicology and Applied Pharmacology

122

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The enzymatic methylation of inorganic As (iAs) is catalyzed by As(+3 oxidation state)-methyltransferase (AS3MT). AS3MT is expressed in rat liver and in human hepatocytes. However, AS3MT is not expressed in UROtsa, human urothelial cells that do not methylate iAs. Thus, UROtsa cells are an ideal null background in which the role of iAs methylation in modulation of toxic and cancer-promoting effects of this metalloid can be examined. A retroviral gene delivery system was used in this study to create a clonal UROtsa cell line (UROtsa/F35) that expresses rat AS3MT. Here, we characterize the metabolism and cytotoxicity of arsenite (iAs III ) and methylated trivalent arsenicals in parental cells and clonal cells expressing AS3MT. In contrast to parental cells, UROtsa/ F35 cells effectively methylated iAs III , yielding methylarsenic (MAs) and dimethylarsenic (DMAs) containing either As III or As V . When exposed to MAs III , UROtsa/F35 cells produced DMAs III and DMAs V . MAs III and DMAs III were more cytotoxic than iAs III in UROtsa and UROtsa/F35 cells. The greater cytotoxicity of MAs III or DMAs III than of iAs III was associated with greater cellular uptake and retention of each methylated trivalent arsenical. Notably, UROtsa/F35 cells were more sensitive than parental cells to the cytotoxic effects of iAs III but were more resistant to cytotoxicity of MAs III . The increased sensitivity of UROtsa/F35 cells to iAs III was associated with inhibition of DMAs production and intracellular accumulation of MAs. The resistance of UROtsa/F35 cells to moderate concentrations of MAs III was linked to its rapid conversion to DMAs and efflux of DMAs. However, concentrations of MAs III that inhibited DMAs production by UROtsa/F35 cells were equally toxic for parental and clonal cell lines. Thus, the production and accumulation of MAs III is a key factor contributing to the toxicity of acute iAs exposures in methylating cells.

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“…48 On the other hand, many studies have indicated that arsenic could alter signaling transduction factors, including NFκB, p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor-α (TNFα), phosphatidydylinositol-3-kinase (PI3K) and PI3K-dependent phosphorylation of protein kinase B (PKB/ Akt), and affecting the insulin-stimulated glucose uptake (ISGU) in adipocytes or skeletal muscle cells, which may potentially link with insulin resistance. [49][50][51][52] PI3K signaling is a pivotal role in the metabolic actions of insulin and its activation regulates multiple signaling transductions. A PI3K-dependent signaling pathway has been demonstrated to exist in β-cells and that it might function to restrain glucose-induced insulin secretion from β-cells.…”

Section: Arsenicmentioning

confidence: 99%

“…However, exposure to low dose of arsenic has been shown to inhibit ISGU in 3T3-L1 adipocytes; the phosphorylation of PKB/Akt was suppressed in exposed cells, which was an important requirement for GLUT4 translocation to the cellular membrane in response to insulin. 51 Moreover, Paul et al 56 have reported that the phosphorylation of PKB/Akt by 3-phosphoinositide dependent kinase 1 (PDK-1) activation was inhibited by treatment with low-dose of arsenic. It has been well known that arsenic has the ability to induce oxidative stress.…”

Section: Arsenicmentioning

confidence: 99%

Heavy metals, islet function and diabetes development

Lin¹,

Yang²,

Huang³

et al. 2009

Islets

208

131

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

Cited by 162 publications

References 65 publications

Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

Heavy metals, islet function and diabetes development

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