A Serum Factor Induces Insulin-Independent Translocation of GLUT4 to the Cell Surface which Is Maintained in Insulin Resistance

Abstract

In response to insulin, glucose transporter GLUT4 translocates from intracellular compartments towards the plasma membrane where it enhances cellular glucose uptake. Here, we show that sera from various species contain a factor that dose-dependently induces GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes, human adipocytes, myoblasts and myotubes. Notably, the effect of this factor on GLUT4 is fully maintained in insulin-resistant cells. Our studies demonstrate that the serum-induced increase in cell surface GLUT4 levels is not due to inhibition of its internalization and is not mediated by insulin, PDGF, IGF-1, or HGF. Similarly to insulin, serum also augments cell surface levels of GLUT1 and TfR. Remarkably, the acute effect of serum on GLUT4 is largely additive to that of insulin, while it also sensitizes the cells to insulin. In accordance with these findings, serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin-induced GLUT4 translocation. We conclude that in addition to insulin, at least one other biological proteinaceous factor exists that contributes to GLUT4 regulation and still functions in insulin resistance. The challenge now is to identify this factor.

Regulation of GLUT4 translocation in an in vitro cell model using postprandial human serum ex vivo

“…The bioactivity of serum on glucose uptake has been observed for decades in multiple cell types (Al‐Khalili et al., ; Berenguer, Martinez, Giorgetti‐Peraldi, Le Marchand‐Brustel, & Govers, ; Bradley & Culp, ; Brodie & Sampson, ; Kletzien & Perdue, ; Pasternak et al., ; Sivitz & Pasley, ), but the underlying mechanism, particularly in response to acute stimulation (≤1 h) in myotubes, is poorly understood. Furthermore, technical limitations owing to low glucose transporter protein abundance and functionality in certain skeletal muscle cell lines have precluded the direct investigation of the bioactivity of human serum on GLUT4 translocation.…”

“…The bioactivity of serum on glucose uptake has been observed for decades in multiple cell types (Al-Khalili et al, 2003;Berenguer, Martinez, Giorgetti-Peraldi, Le Marchand-Brustel, & Govers, 2010;Bradley & Culp, 1974;Brodie & Sampson, 1991;Kletzien & Perdue, 1973;Pasternak et al, 1991;Sivitz & Pasley, 1995), but the underlying mechanism, particularly in response to acute stimulation important regulator of glucose uptake in response to chronic, but not acute, incubation with serum (Kleitzien & Perdue, 1974). Although a sustained increase in cellular glucose uptake after prolonged exposure to serum requires de novo protein synthesis, the acute stimulatory effect of serum on glucose uptake (<1.5 h) is insensitive to cycloheximide (Kleitzien & Perdue, 1974).…”

Deciphering the role of GLUT4 N-glycosylation in adipocyte and muscle cell models

“…To express HA-GLUT4 in preadipocytes and adipocytes, preadipocytes were infected with retrovirus as described previously [22], except that Plat-E cells were used for the production of virus [24]. L6 myoblasts were cultured as described previously [25], infected with retrovirus for the expression of HA-GLUT4, and used for experiments before reaching confluence. Adipocytes were used for experiments 8-12 days after the onset of differentiation, with medium renewed 2 days before the experiment.…”

Hepatocyte growth factor alleviates hepatic insulin resistance and lipid accumulation in high‐fat diet‐fed mice

“…In recent years, HGF has been suggested to be favorable in obesity, insulin resistance and metabolic syndrome, and was defined as an important regulator in type 2 diabetes. Several clinical studies showed that serum levels of HGF were correlated with fasting blood glucose, triglycerides, blood pressure, progression of insulin resistance and the presence of type 2 diabetes. In vivo studies, β‐cells‐Met −/− mice showed apparent hyperglycemia and an impaired response to insulin.…”