Hyperglycemia Potentiates H2O2 Production in Adipocytes and Enhances Insulin Signal Transduction: Potential Role for Oxidative Inhibition of Thiol-Sensitive Protein-Tyrosine Phosphatases Export

@article{citeulike:4075856, abstract = {Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H2O2) that facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs) that are negative regulators of insulin action. As hyperglycemia is associated with increased cellular reactive oxygen species, we postulated that high glucose conditions might potentiate the H2O2 generated by insulin and modulate insulin-stimulated protein phosphorylation. Basal H2O2 generation was increased threefold in differentiated 3T3-L1 adipocytes by growth in 25 mM glucose versus 5 mM glucose. High glucose increased the sensitivity of the insulin-stimulated H2O2 signal to lower concentrations of insulin. Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. In primary rat adipocytes, high glucose increased insulin-stimulated H2O2 production and potentiated the oxidative inhibition of total PTP and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). These studies indicate that high glucose can enhance insulinstimulated H2O2 generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC. Antioxid. Redox Signal. 7, 526–537.}, author = {Wu, Xiangdong and Zhu, Li and Zilbering, Assaf and Mahadev, Kalyankar and Motoshima, Hiroyuki and Yao, Junli and Goldstein, Barry J.}, citeulike-article-id = {4075856}, citeulike-linkout-0 = {http://dx.doi.org/10.1089/ars.2005.7.526}, citeulike-linkout-1 = {http://www.liebertonline.com/doi/abs/10.1089/ars.2005.7.526}, doi = {10.1089/ars.2005.7.526}, journal = {Antioxidants \& Redox Signaling}, keywords = {adipocytes, h2o2, hyperglycemia, insulin\_resistance}, number = {5-6}, pages = {526--537}, posted-at = {2009-02-20 23:32:18}, priority = {3}, title = {Hyperglycemia Potentiates H2O2 Production in Adipocytes and Enhances Insulin Signal Transduction: Potential Role for Oxidative Inhibition of Thiol-Sensitive Protein-Tyrosine Phosphatases}, url = {http://dx.doi.org/10.1089/ars.2005.7.526}, volume = {7}, year = {2005} }

TY - JOUR ID - citeulike:4075856 L3 - citeulike-article-id:4075856 N2 - Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H2O2) that facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs) that are negative regulators of insulin action. As hyperglycemia is associated with increased cellular reactive oxygen species, we postulated that high glucose conditions might potentiate the H2O2 generated by insulin and modulate insulin-stimulated protein phosphorylation. Basal H2O2 generation was increased threefold in differentiated 3T3-L1 adipocytes by growth in 25 mM glucose versus 5 mM glucose. High glucose increased the sensitivity of the insulin-stimulated H2O2 signal to lower concentrations of insulin. Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. In primary rat adipocytes, high glucose increased insulin-stimulated H2O2 production and potentiated the oxidative inhibition of total PTP and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). These studies indicate that high glucose can enhance insulinstimulated H2O2 generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC. Antioxid. Redox Signal. 7, 526–537. IS - 5-6 JF - Antioxidants & Redox Signaling EP - 537 TI - Hyperglycemia Potentiates H2O2 Production in Adipocytes and Enhances Insulin Signal Transduction: Potential Role for Oxidative Inhibition of Thiol-Sensitive Protein-Tyrosine Phosphatases VL - 7 SP - 526 KW - adipocytes KW - h2o2 KW - hyperglycemia KW - insulin_resistance AU - Wu, Xiangdong AU - Zhu, Li AU - Zilbering, Assaf AU - Mahadev, Kalyankar AU - Motoshima, Hiroyuki AU - Yao, Junli AU - Goldstein, Barry PY - 2005/// UR - http://dx.doi.org/10.1089/ars.2005.7.526 ER -