Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo(-/-)) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-alpha for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-alpha. Vitamin C deficiency aggravated TNF-alpha-induced insulin resistance in Gulo(-/-) mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3 beta) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-a-treated Gulo(-)(/-) mice. In HepG2 cells, vitamin C reversed the TNF-alpha-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3 beta pathway. Furthermore, vitamin C inhibited the TNF-alpha-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-kappa B) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders.