Improvement of Insulin Resistance by Removal of Systemic Hydrogen Peroxide by PEGylated Catalase in Obese Mice
ABSTRACT Insulin resistance, a condition in which insulin action is impaired, is one of the characteristic features of type 2 diabetes. Excessive amounts of reactive oxygen species (ROS) interfere with the insulin signaling pathway, which leads to the progression of insulin resistance. To examine whether removal of systemic hydrogen peroxide is effective in improving insulin resistance, polyethylene glycol-conjugated catalase (PEG-catalase), a derivative with a long circulation half-life, was repeatedly injected into leptin-deficient ob/ob or high fat diet-induced obese mice for 16 or 10 consecutive weeks, respectively. Although ob/ob mice gradually gained weight with time irrespective of the treatment, repeated intraperitoneal injections of PEG-catalase significantly reduced glucose levels in the fed state. Glucose and insulin tolerance tests also showed PEG-catalase significantly improved glucose tolerance and insulin sensitivity in ob/ob mice, respectively. Similar but less marked results were obtained in the diet-induced obese mice. Treatment of 3T3-L1 adipocytes with glucose oxidase (GO) increased lipid hydroperoxide formation and reduced insulin-stimulated Akt phosphorylation. Addition of catalase or PEG-catalase significantly inhibited the GO-induced changes in adipocytes. These findings indicate that systemic removal of hydrogen peroxide by PEG-catalase activates the insulin signaling pathway and improves insulin resistance in obese mice.
SourceAvailable from: Sebastian MuellerZeitschrift für Gastroenterologie 01/2008; 46(01). DOI:10.1055/s-2008-1037551 · 1.67 Impact Factor
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ABSTRACT: Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes.Journal of Controlled Release 06/2013; 170(2). DOI:10.1016/j.jconrel.2013.05.028 · 7.26 Impact Factor
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ABSTRACT: Superoxide dismutase (SOD) and catalase activities of a drug are of great importance for its effective protection against reactive oxygen species (ROS)-induced injury. Achievement of catalase activity of a synthetic compound remains a challenge. Water-soluble Mn-porphyrins have high SOD and peroxynitrite (ONOO(-)) reducing activities, but not catalase-like activity. Herein, we are able to retain the fair SOD-like activity of a mononuclear Mn-5-(N-methylpyridinium-4-yl)-10,15,20-triphenyl porphyrin (MnM4PyP3P), while gaining in catalase-like activity with its dinuclear complex, 1,3-di[5-(N-methylene-pyridinium-4-yl)-10,15,20-triphenyl porphynato manganese] benzene tetrachloride (MnPD). Mechanistic study indicates that catalase-like activity of MnPD is due to synergism of two Mn active sites, where hydroxo-Mn(IV) complex is formed as an intermediate. The in vivo experiments demonstrate that MnPD significantly restores the treadmill-running ability of SOD-deficient mouse and thus indicates the therapeutic potential of MnPD. Furthermore, MnPD may serve as a mechanistic tool and indicate the new directions in the synthesis of catalase-like mimics.ACS Medicinal Chemistry Letters 06/2014; 5(6):639-43. DOI:10.1021/ml400493f · 3.07 Impact Factor