Effect of thiol antioxidant on body fat and insulin reactivity

Hildebrandt, Wulf; Hamann, Andreas; Krakowski-Roosen, Holger; Kinscherf, Ralf; Dugi, Klaus A.; Sauer, Roland; Lacher, Sabrina; Nöbel, Nuria; Bodens, Anne; Bellou, Vassiliki; Edler, Lutz; Nawroth, Peter; Dröge, Wulf

doi:10.1007/s00109-004-0532-5

Cited by 43 publications

(63 citation statements)

References 41 publications

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“…Even relatively small changes in absolute autophosphorylation rates may significantly alter the delicate balance between muscle and adipose tissues with respect to insulin responsiveness and fuel deposition. This conclusion is supported by a recent clinical study of non-diabetic obese subjects (48) showing that (i) obesity is associated with abnormally low plasma thiol (mainly cysteine) levels; (ii) insulin reactivity is decreased in patients supplemented with N-acetylcysteine; and (iii) glucose clearance, i.e. the bona fide indicator of the insulin reactivity of muscle cells, is increased by simultaneous treatment with creatine if the patients are treated with N-acetylcysteine but not with placebo.…”

Section: Discussionsupporting

confidence: 65%

“…the bona fide indicator of the insulin reactivity of muscle cells, is increased by simultaneous treatment with creatine if the patients are treated with N-acetylcysteine but not with placebo. Moreover, the mean HOMA-R index, which is defined as (fasting plasma glucose (mg/dl) ϫ fasting plasma insulin concentration (milliunits/ml)) ϫ 405 Ϫ1 and which is therefore an inverse indicator of insulin reactivity in the postabsorptive period, was found to be increased in the group with N-acetylcysteine plus placebo but decreased in the group with N-acetylcysteine plus creatine (48). N-Acetylcysteine treatment with or without creatine supplementation or treatment with a cysteine-rich protein has been shown to cause a decrease in body fat (48 -50), suggesting that the redox regulation of IRK activity may contribute to the development of obesity.…”

Section: Discussionmentioning

confidence: 97%

“…The finding that hydrogen peroxide or an oxidative shift in the thiol/disulfide redox status increases IRK autophosphorylation in the absence of insulin further suggests that the insulinindependent IR "basal activity" may increase in old age and other conditions associated with an oxidative shift in the plasma thiol/disulfide redox status (44,48). A decrease in IR signaling was recently found to increase longevity and stress resistance in various species (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

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Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide

Schmitt

Hotz‐Wagenblatt

Klein

et al. 2005

Journal of Biological Chemistry

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Insulin signaling requires autophosphorylation of the insulin receptor kinase (IRK) domain. Using purified recombinant IRK fragments and the isolated intact insulin receptor, we show here that autophosphorylation is inhibited by ADP and that this effect is essentially reversed by hydrogen peroxide. Autophosphorylation was inhibited by hydrogen peroxide (60 M) in the absence of ADP but enhanced in the presence of inhibitory concentrations of ADP (67 M). Enhancement by hydrogen peroxide required direct interaction of hydrogen peroxide with the kinase domain and was not seen in insulin receptor mutants C1245A and C1308A. A similar enhancement was obtained in intact cells in the absence of insulin upon treatment with 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea, indicating that IRK activity can be alternatively enhanced by a shift in the thiol/ disulfide redox status. Molecular modeling of the IRK domain indicated that the ATP-binding site becomes distorted after releasing the nucleotide unless the IRK domain is oxidatively derivatized at Cys 1245 . Recent clinical studies suggest that these effects may play a role in obesity due to the fact that cytoplasmic creatine kinase in combination with phosphocreatine normally ensures rapid removal of ADP in muscle cells but not in fat cells. Stimulation of insulin receptor kinase (IRK)1 activity typically involves binding of insulin to the extracellular ␣-subunits of the insulin receptor, which leads to autophosphorylation of the intracellular ␤-subunits (1). The crystal structures of the non-phosphorylated IRK domain (IRK-0P; "gate-closed" conformation) and the trisphosphorylated IRK domain (IRK-3P; "gate-open" conformation) have been described (2, 3). Dimerization of the IRK domain (4) or high concentrations of adenosine nucleotides (3, 5, 6) were found to favor the gate-open conformation even in the absence of autophosphorylation. The action of IRK can be down-regulated by a redox-sensitive protein-tyrosine phosphatase (7,8). Brief exposure of cells to hydrogen peroxide was shown to increase insulin receptor autophosphorylation. In some studies, this effect was shown to involve the oxidative inactivation of protein-tyrosine phosphatase activity (7-13). The physiological significance of the role of hydrogen peroxide was underscored by the finding that insulin stimulates the formation of superoxide radicals and their derivative hydrogen peroxide by NAD(P)H oxidase in adipocytes (7, 14 -17). An important role of hydrogen peroxide in insulin signaling was also suggested by the finding that mice overexpressing cellular glutathione peroxidase develop insulin resistance (18).Earlier studies have shown that IRK activity is increased or suppressed by sulfhydryl-reactive agents such as iodoacetamide, maleimidobutyrylbiocytin, and N-ethylmaleimide (19 -22), suggesting that the IRK domain may contain one or more functionally important cysteine residues. Treatment of cells with the glutathione reductase inhibitor 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (BCNU), which ...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide

Schmitt

Hotz‐Wagenblatt

Klein

et al. 2005

Journal of Biological Chemistry

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“…In addition to the increased production of reactive oxygen species (ROS) in DM, the antioxidant capacity is decreased, and oxidative stress is associated with obesity and insulin resistance (4,15,21,26,47). Therefore, treatment with antioxidants or overexpression of antioxidant enzymes can, at least partially, prevent oxidative stressinduced insulin resistance (20,24,26,36).…”

mentioning

confidence: 99%

Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor γ in Human Skeletal Muscle Cells

Chung

Kim

Youn

et al. 2009

Molecular and Cellular Biology

165

125

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Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferatoractivated receptor ␥ (PPAR␥) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPAR␥ induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H 2 O 2 levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulinresistant cells, suggesting that GPx3 is required for the regulation of PPAR␥-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPAR␥ is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.

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“…Incisional site become transient ischemic state and then occur reoxygenation due to vasodilatation by inflammatory reaction, the productive reactive oxygen species (ROS) give rise to many physiologic results [5].…”

Section: 대한치과마취과학회지 제14권 제3호 157-165mentioning

confidence: 99%

The Effect of Remifentanil Preconditioning on Injured Keratinocyte

Hong

Kim

Yoon

et al. 2014

J Korean Dent Soc Anesthesiol

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Background: Incisional site of surgical operation become transient ischemic state and then occur reoxygenation due to vasodilatation by inflammatory reaction, the productive reactive oxygen species (ROS) give rise to many physiologic results. Apoptosis have major role on elimination of inflammatory cell and formation of granulation tissue in normal wound healing process. Remifentanil can prevent the inflammatory response and can suppress inducible nitric oxide synthase expression in a septic mouse model. After cardiopulmonary bypass for coronary artery surgery, remifentanil can also inhibit the release of biomarkers of myocardial damage. Here we investigated whether remifentanil pretreatment has cellular protective effect against hypoxia-reoxygenation in HaCaT human keratinocytes, if so, the role of apoptosis and autophagy on this phenomenon. Methods: The HaCaT human keratinocytes were exposed to various concentrations of remifentanil (0.01, 0.05, 0.1, 0.5 and 1 ng/ml) for 2 h before hypoxia (RPC/HR group). These cells were cultured under 1% oxygen tension for 24h at 37°C. After hypoxia, to simulate reoxygenation and recovery, the cells were reoxygenated for 12 h at 37°C. 3-MA/RPC/HR group was treated 3-methyladenine (3-MA), autophagy inhibitor for 1h before remifentanil treatment. Cell viability was measured using a quantitative colorimetric assay with thiazolyl blue tetrazoliumbromide (MTT, amresco), showing the mitochondrial activity of living cells. To investigate whether the occurrence of autophagy and apoptosis, we used fluorescence microscopy and Western blot analysis. Results: The viability against hypoxia-reoxygenation injury in remifentanil preconditioning keratinocytes were increased, and these cells were showed stimulated expression of autophagy 3-MA suppressed the induction of autophagy effectively and the protective effects on apoptosis. Atg5, Beclin-1, LC3-II and p62 were elevated in RPC/HR group. But they were decreased when autophagy was suppressed by 3-MA. Conclusions: Remifentanil preconditioning showed the protective effect in human keratinocytes, and we concluded that autophagy may take the major role in the recovery of wound from hypoxia-reoxygenation injury. We suggest that further research is needed about the cell protective effects of autophagy.

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Effect of thiol antioxidant on body fat and insulin reactivity

Cited by 43 publications

References 41 publications

Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide

Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide

Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor γ in Human Skeletal Muscle Cells

The Effect of Remifentanil Preconditioning on Injured Keratinocyte

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