The growth of obesity over the past decades is associated with increased incidence of several diseases directly associated with excessive adipose tissue mass, such as, insulin resistance and Type 2 Diabetes. Despite of the recent advances in the elucidation of the molecular mechanism involved in the development of insulin resistance, few pharmacological approaches are available to prevent and treat this disease. Recently, repositories and large-scale drug screening platforms have been used with success in the discovery of new therapies for a great number of diseases. Since more efficient therapies are needed for insulin resistance treatment, the aim of this study is develop a new large-scale platform for drug screening, attempting to identify drugs approved by FDA that could improve insulin sensitivity and insulin-stimulated glucose uptake in skeletal muscle cell line (L6). Therefore, 727 FDA approved drugs used to treat several diseases such as cancer, cardiovascular and renal diseases, from NIH (National Institue of Heath) libraries, will be tested to identify those that attenuate the insulin resistance induced by TNF-±/dexametasone cocktail. We chose to screen libraries of drugs that are in clinical use and cover a large diversity of biological events aiming to accelerate the translational process. Drugs that augment insulin sensitivity in L6 cells will be validated in a secondary screen, where they will be assessed for cell viability, molar concentration which induces 50% of maximal glucose uptake (EC50), and metabolic effects on adipocyte cell line. Furthermore, we will evaluate the effect of potencial drugs in canonical insulin signalling pathway and gene expression of inflammatory cytokines in L6 cell line. Finally, we will test drug efficacy to improve insulin sensitivity and insulin signalling transduction and to attenuate inflammatory cytokine gene expression in skeletal muscle in a preclinical in vivo model.
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