The anabolic hormone insulin promotes glucose uptake by triggering the translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the cell surface through exocytosis. Upon the termination of insulin signaling, GLUT4 gradually returns to intracellular storage compartments through endocytosis. Defects in GLUT4 translocation are a hallmark of insulin resistance (IR) and type 2 diabetes (T2D). Our team has performed genome-scale genetic screens to systematically dissect GLUT4 exocytosis and endocytosis. The screens recovered known GLUT4 trafficking regulators but most of the hits were not previously linked to the GLUT4 pathway. A regulator of GLUT4 endocytosis identified in the screens is AAGAB, a soluble factor of 34 kDa. AAGAB controls the stepwise assembly of AP2 adaptor, a central cargo adaptor in clathrin-mediated endocytosis. Unexpectedly, we found that AAGAB also binds to Munc18c and directly inhibits SNARE-Munc18-mediated GLUT4 vesicle fusion. Thus, AAGAB plays a dual role in GLUT4 trafficking. I will also discuss OSBPL8 and OSBPL10, two negative regulators of GLUT4 translocation identified in our screens. OSBPL8 and OSBPL10 are putative lipid transfer proteins operating between intracellular organelles. We propose that OSBPL8 and OSBPL10 regulate lipid dynamics required for insulin signaling, thereby influencing the activities of GLUT4 exocytic regulators. These genetic studies will likely facilitate the identification of new therapeutic targets for IR and T2D.


J. Shen: None.


American Diabetes Association (1-19-IBS-305); National Institutes of Health (DK095367, GM126960)

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