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Novel d-Xylose Derivatives Stimulate Muscle Glucose Uptake by Activating AMP-Activated Protein Kinase α

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journal contribution
posted on 2008-12-25, 00:00 authored by Arie Gruzman, Ofer Shamni, Moriya Ben Yakir, Daphna Sandovski, Anna Elgart, Evgenia Alpert, Guy Cohen, Amnon Hoffman, Yehoshua Katzhendler, Erol Cerasi, Shlomo Sasson
Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that d-xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myotubes in vitro. Due to the unfavorable pharmacokinetic properties of d-xylose we aimed at synthesizing active derivatives with improved parameters. Quantitative structure−activity relationship analysis identified critical hydroxyl groups in d-xylose. These data were used to synthesize various hydrophobic derivatives of d-xylose of which compound 19 the was most potent compound in stimulating the rate of hexose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of myotubes. This effect resulted from the activation of AMP-activated protein kinase without recruiting the insulin transduction mechanism. These results show that lipophilic d-xylose derivatives may serve as prototype molecules for the development of novel antihyperglycemic drugs for the treatment of diabetes.