339-OR: UNC119B: A Novel Target for the Treatment of Type 2 Diabetes

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Introduction and Objective: Following our discovery of compound C59 as a new insulin sensitizer, we identified Unc119b as its molecular target. The role of Unc119b in insulin signaling had not previously been shown. Here we investigate how Unc119b regulates GLUT4 translocation and validate Unc119b as a novel promising target to improve insulin sensitivity. Methods: To test insulin action, we measured glucose tolerance, insulin tolerance and glucose uptake. Unc119b expression was measured by qPCR and western blot. Activity of Rac1 was measured through PAK1 pull down and PAK1 phosphorylation assays. Results: We found that Unc119b silencing enhances insulin-stimulated GLUT4-translocation in cells and that deletion of Unc119b significantly improves glucose tolerance and glucose uptake in skeletal muscle and BAT of rodent models of insulin resistance. Of note, we show that Unc119b expression is increased in those tissues in obese animals. Mechanistically, we show that Unc119b binds to Rac1, a small Rho-GTPase which facilitates GLUT4 translocation. Inhibition of Unc119b using C59 results in increased activation of Rac1 by insulin and increased phosphorylation of its downstream effector PAK1. Conclusion: These results suggest that Unc119b impairs insulin action through inhibition of Rac1and that the increased expression of Unc119b in obese individuals likely contributes to the development of insulin resistance. Genetic or pharmacological inhibition of Unc119b significantly improved insulin sensitivity and glucose tolerance through enhanced Rac1 signaling and increased GLUT4 translocation in skeletal muscle and BAT. Together, these data establish Unc119b as a promising new target for the treatment of insulin resistance and type II diabetes. Disclosure A. Mittal: None. P. Buscaglia: None. J. Sebag: None. Funding National Institutes of Health (RO1DK138932)

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