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  • Title: Effect of a novel non-thiazolidinedione peroxisome proliferator-activated receptor alpha/gamma agonist on glucose uptake.
    Author: Hu X, Feng Y, Liu X, Zhao XF, Yu JH, Yang YS, Sydow-Bäckman M, Hörling J, Zierath JR, Leng Y.
    Journal: Diabetologia; 2007 May; 50(5):1048-57. PubMed ID: 17333104.
    Abstract:
    AIMS/HYPOTHESIS: The effect of the benzopyran derivative T33, a novel non-thiazolidinedione agent, was studied on peroxisome proliferator-activated receptors (PPARs), insulin signalling and glucose uptake in adipocytes and skeletal muscle. We hypothesised that T33 could activate PPARgamma and exert a beneficial effect on insulin action on glucose uptake and lipid metabolism. MATERIALS AND METHODS: Using a cell-based reporter gene assay, T33 was identified as a PPARalpha/gamma dual agonist, which activated human PPARgamma and PPARalpha with EC50 values of 19 and 148 nmol/l, respectively. The effect of T33 on glucose metabolism was studied in cultured 3T3-L1 adipocytes and L6 myotubes. In vivo effects of T33 on skeletal muscle were determined in ob/ob mice treated with 8 mg/kg T33. The effect of T33 on metabolic abnormalities was observed in diet-induced obese mice. RESULTS: Exposure of 3T3-L1 adipocytes to T33 for 4 days increased basal and insulin-stimulated glucose uptake, with no effect noted in L6 myotubes. Treatment of ob/ob mice for 20 days with T33 normalised basal and insulin-stimulated glucose uptake and increased phosphorylation of Akt and p38 mitogen-activated protein kinase in skeletal muscle. In contrast, phosphorylation of AMP-activated protein kinase was unaltered. Moreover, T33 improved insulin sensitivity and lipid metabolism in diet-induced obese mice. CONCLUSIONS/INTERPRETATION: T33 is non-thiazolidinedione PPARalpha/gamma dual agonist which directly increases basal and insulin-stimulated glucose uptake in adipocytes and secondarily improves insulin action on insulin signalling and glucose metabolism in skeletal muscle from diabetic ob/ob mice.
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