Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin
Debate exists regarding the role of resistin in the pathophysiology of insulin resistance. The aim of this study was to directly assess the effects of resistin (0–24 h) on basal and insulin-stimulated glucose uptake and metabolism in skeletal muscle cells and to investigate the mechanisms responsible for the effects of resistin.
We used L6 rat skeletal muscle cells and examined [3H]2-deoxyglucose uptake, GLUT4 translocation and GLUT protein content. We assessed glucose metabolism by measuring the incorporation of D-[U-14C]glucose into glycogen, 14CO2 and lactate production, as well as the phosphorylation level and total protein content of insulin signalling proteins, including insulin receptor β-subunit (IRβ), insulin receptor substrate (IRS), Akt and glycogen synthase kinase-3β (GSK-3β).
Treatment of L6 rat skeletal muscle cells with recombinant resistin (50 nmol/l, 0–24 h) reduced levels of basal and insulin-stimulated 2-deoxyglucose uptake and decreased insulin-stimulated GLUT4myc content at the cell surface, with no alteration in the production of GLUT4 or GLUT1. Resistin also decreased glycogen synthesis and GSK-3β phosphorylation. Insulin-stimulated oxidation of glucose via the Krebs cycle was reduced by resistin, whereas lactate production was unaltered. Although insulin receptor protein level and phosphorylation were unaltered by resistin, production of IRS-1, but not IRS-2, was downregulated and a decreased tyrosine phosphorylation of IRS-1 was detected. Reduced phosphorylation of Akt on T308 and S473 was observed, while total Akt and Akt1, but not Akt2 or Akt3, production was decreased.
Our data show that resistin regulates the function of IRS-1 and Akt1 and decreases GLUT4 translocation and glucose uptake in response to insulin. Selective decreases in insulin-stimulated glucose metabolism via oxidation and conversion to glycogen were also induced by resistin. These observations highlight the potential role of resistin in the pathophysiology of type 2 diabetes in obesity.
- Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin
Volume 49, Issue 1 , pp 183-190
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