Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation

Abstract

. Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am J Physiol Endocrinol Metab 285: E106-E115, 2003. First published March 4, 2003 10.1152/ajpendo.00457.2002-Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulinstimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-␣, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters. skeletal muscle; glucose transporter-4

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

“…Here we further investigated the role of resistin in regulating basal and insulin-stimulated glucose uptake and metabolism in rat skeletal muscle cells by examining the effect of resistin treatment times up to 24 h. We have shown that resistin caused a decrease in both basal and insulinstimulated glucose uptake. This expands upon our previous work [25] using shorter resistin pretreatment times and is similar to studies performed in adipocytes [6,17]. Furthermore, we measured the cell surface content of myctagged GLUT4 in intact cells to identify that the mechanism underlying the effect of resistin on insulin-stimulated glucose uptake involved a decrease in the extent of translocation of GLUT4 to the cell surface.…”

“…Importantly, this was associated with whole body insulin resistance and decreased IRS-1 phosphorylation in muscle [32], although it was suggested that these in vivo effects of resistin may be mediated via increased TNF-α production. We have also recently demonstrated that resistin acutely decreased glucose uptake in skeletal muscle cells [25].…”

“…Although results from both ourselves [25] and others [6] have established the ability of acute resistin treatment to reduce glucose uptake in muscle and fat, few studies have examined the direct effect of chronic resistin on glucose uptake. We believe that because chronic hyperresistinaemia is typically found in obese animals and humans that chronic effects are more pertinent to the pathophysiology of diabetes.…”

“…This work, which involves various periods of resistin treatment (0-24 h), follows up our initial work examining the effects of acute resistin treatment [25].…”

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

“…In particular, a reduction of intrinsic GLUT4 activity has been suggested to be a contributor to insulin resistance in obese diabetic subjects (Alkhateeb et al, 2007). In L6 muscle cells, insulin-stimulated glucose transport was reduced by altering the intrinsic activity of cell surface GLUT4 without change of GLUT4 translocation and Akt phosphorylation (Moon et al, 2003). In addition to reduced intrinsic activity, the downregulation of GLUT4 expression may play a role in the induction of insulin resistance (Garvey et al, 1992;Karnieli and Armoni, 2008;Shepherd and Kahn, 1999).…”