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

Abstract

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-α (TNF-α)-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-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-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-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo-/- mice. In HepG2 cells, vitamin C reversed the TNF-α-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/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) 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.

• Authors: Zhou Qing, Wu Xiao-Hui, Wu Xi-Mei, Zou Chao-Chun
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 829 Pg. 1-11 (Jun 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 29625084 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• NF-kappa B
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• NF-KappaB Inhibitor alpha
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• I-kappa B Kinase
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Glucose
• Ascorbic Acid

Topics

• Animals
• Ascorbic Acid (pharmacology)
• Ascorbic Acid Deficiency (metabolism, pathology)
• Enzyme Activation (drug effects)
• Gene Expression Regulation (drug effects)
• Glucose (metabolism)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Hep G2 Cells
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• I-kappa B Kinase (metabolism)
• Insulin Resistance
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Liver (drug effects, metabolism)
• Male
• Mice
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)