Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin

Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter (GLUT)4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanism behind acute induction has been unclear in other systems. Thioredoxin interacting protein (TXNIP) has been shown to be a negative regulator of cellular glucose uptake. TXNIP is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that TXNIP is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, TXNIP serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4. [Display omitted] •TXNIP is a substrate of AKT•TXNIP facilitates GLUT4 endocytosis•Growth factors induce acute glucose uptake in cells via regulating TXNIP Waldhart et al. find that TXNIP, an α-arrestin protein, is an adaptor for endocytosis of the glucose transporter GLUT4. Growth factor stimulation induces acute glucose uptake into cells by activating AKT-mediated TXNIP phosphorylation, forcing TXNIP to dissociate from the transporters, thus inhibiting their endocytosis.