TNF-α impairs insulin signaling and insulin stimulation of glucose uptake in C2C12muscle cells

Abstract

Physiological stressors such as sepsis and tissue damage initiate an acute immune response and cause transient systemic insulin resistance. This study was conducted to determine whether tumor necrosis factor-α (TNF-α), a cytokine produced by immune cells during skeletal muscle damage, decreases insulin responsiveness at the cellular level. To examine the molecular mechanisms associated with TNF-α and insulin action, we measured insulin receptor substrate (IRS)-1- and IRS-2-mediated phosphatidylinositol 3-kinase (PI 3-kinase) activation, IRS-1-PI 3-kinase binding, IRS-1 tyrosine phosphorylation, and the phosphorylation of two mitogen-activated protein kinases (MAPK, known as p42MAPK and p44MAPK) in cultured C2C12myotubes. Furthermore, we determined the effects of TNF-α on insulin-stimulated 2-deoxyglucose (2-DG) uptake. We observed that TNF-α impaired insulin stimulation of IRS-1- and IRS-2-mediated PI 3-kinase activation by 54 and 55% ( P< 0.05), respectively. In addition, TNF-α decreased insulin-stimulated IRS-1 tyrosine phosphorylation by 40% ( P < 0.05). Furthermore, TNF-α repressed insulin-induced p42MAPKand p44MAPK tyrosine phosphorylation by 81% ( P < 0.01). TNF-α impairment of insulin signaling activation was accompanied by a decrease ( P < 0.05) in 2-DG uptake in the muscle cells (60 ± 4 vs. 44 ± 6 pmol ⋅ min−1 ⋅ mg−1). These data suggest that increases in TNF-α may cause insulin resistance in skeletal muscle by inhibiting IRS-1- and IRS-2-mediated PI 3-kinase activation as well as p42MAPK and p44MAPK tyrosine phosphorylation, leading to impaired insulin-stimulated glucose uptake.