Improvement of Insulin Resistance by Removal of Systemic Hydrogen Peroxide by PEGylated Catalase in Obese Mice
Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Molecular Pharmaceutics
(Impact Factor: 4.38).
10/2010; 7(6):2069-76. DOI: 10.1021/mp100110c
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.
Available from: Pierre Watcho
- "Dissecting a relative contribution of impaired glucose tolerance/overt hyperglycemia vs dyslipidemia to complications associated with Type 2 diabetes or prediabetes is quite challenging, as a vast majority of therapeutic agents affects both carbohydrate and lipid metabolism. Niacin reduces triglyceride concentration by inhibiting hepatic synthesis of fatty acids and triglycerides, and hepatic VLDL secretion as well as release of fatty acids from adipose tissue  . In a clinical study in 468 participants including 125 with diabetes mellitus , niacin improved lipid profile, without affecting blood glucose control, in human subjects with and without diabetes. "
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ABSTRACT: Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome before overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased nonesterified fatty acids (NEFA), and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative-nitrosative stress. Sixteen-week-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100 mg kg(-1) day(-1), 4 weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit and changes in behavioral measures of sensory function and corrected oxidative-nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative-nitrosative stress. Lipid-lowering agents and antioxidants may find a use in the management of this condition.
Free Radical Biology and Medicine 02/2012; 52(8):1255-63. DOI:10.1016/j.freeradbiomed.2012.01.029 · 5.74 Impact Factor
Available from: Sebastian Mueller
Zeitschrift für Gastroenterologie 01/2008; 46(01). DOI:10.1055/s-2008-1037551 · 1.05 Impact Factor
Available from: Yuki Takahashi
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ABSTRACT: Surgical trauma, which is inevitably associated with the surgical removal of cancer, has been reported to accelerate tumor metastasis. The close association of reactive oxygen species with the trauma and tumor metastasis supports the possibility of using antioxidants for the inhibition of metastasis. To inhibit surgical trauma-enhanced peritoneal dissemination, human catalase (hCAT) derivatives, i.e., hCAT-nona-arginine peptide (hCAT-R9) and hCAT-albumin-binding peptide (hCAT-ABP), were designed to increase the retention time of the antioxidant enzyme in the abdominal cavity after intraperitoneal administration. Both (125)I-labeled derivatives showed significantly prolonged retention in the cavity compared to (125)I-hCAT. Cauterization of the cecum of mice with a hot iron, an experimental model of surgical trauma, induced abdominal adhesions. In addition, cauterization followed by colon26 tumor cell inoculation increased lipid peroxidation in the cecum and mRNA expression of molecules associated with tissue repair/adhesion and inflammation in the peritoneum. hCAT derivatives significantly suppressed the increased mRNA expression. The cauterization also increased the number of tumor cells in the abdominal organs, and the number was significantly reduced by hCAT-R9 or hCAT-ABP. These results indicate that hCAT-R9 and hCAT-ABP, both of which have a long retention time in the peritoneal cavity, can be effective at inhibiting surgery-induced peritoneal metastasis.
Free Radical Biology and Medicine 05/2011; 51(3):773-9. DOI:10.1016/j.freeradbiomed.2011.05.025 · 5.74 Impact Factor
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