Insulin promotes glucose uptake by triggering the translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the cell surface through exocytosis. Defects in GLUT4 exocytosis are a hallmark of insulin resistance (IR) and type 2 diabetes (T2D). To develop effective and safe treatments for IR and T2D, it is crucial to gain a comprehensive understanding of insulin-stimulated GLUT4 exocytosis at the molecular level. Recently, our group developed new genetic screen platforms to systematically dissect insulin-stimulated GLUT4 exocytosis, taking advantage of the revolutionary CRISPR-Cas9 genome editing system. Our genome-wide CRISPR screens recovered known GLUT4 exocytic regulators but most of the hits were not previously linked to the GLUT4 exocytic pathway. Here, I will focus on AAGAB, a negative regulator of GLUT4 translocation identified in the screens. We discovered that AAGAB plays a dual role in GLUT4 trafficking: 1) it promotes the endocytosis of GLUT4, and 2) it negatively regulates the SNARE-Munc18-mediated GLUT4 vesicle fusion. In addition, I will discuss OSBPL8 and OSBPL10, another two negative regulators 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 facilitate the identification of new therapeutic targets for IR and T2D.


J. Shen: None.


National Institutes of Health

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