FRI617 Targeting Unc119b For Insulin Sensitization

Disclosure: A. Mittal: None. P. Buscaglia: None. J.A. Sebag: None. Using high-throughput screening, we identified a new insulin sensitizer, C59, which enhances insulin-stimulated GLUT4 translocation and glucose uptake in glucose storage tissues. C59 treatment improves glucose tolerance in rodent models of insulin resistance. Using Proteome Integral Stability Assay we identified Unc119B as the molecular target of C59. Interaction of C59 with Unc119 was further confirmed by solving the crystal structure of C59 bound Unc119. Unc119B, a protein involved in intracellular trafficking of lapidated cargos, has not previously been implicated in the regulation of glucose homeostasis. Here, we show that deletion of Unc119B protects mice from high fat diet induced insulin resistance compared to DIO WT mice despite similar weight gain, thus, further suggesting an important role of this protein in glucose handling. To understand the mechanism through which Unc119b may inhibit insulin-stimulated GLUT4 translocation, we tested its interaction with TC10α, a prenylated small G-protein that plays a critical role in GLUT4 translocation. Co-immunoprecipitation in CHO cells revealed that Unc119B forms a complex with TC10α. Our results identify Unc119B as a new important regulator of GLUT4 translocation and suggest that it may be acting through the regulation of TC10α activity. This work also identifies Unc119b as a new promising target for the treatment of pre-diabetes and type II diabetes. Presentation: Friday, June 16, 2023