Mechanisms of TNF-α-induced insulin resistance

Abstract

There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.

Anti‐inflammatory and anti‐insulin resistance activities of aqueous extract from Anoectochilus burmannicus

“…In animal model, several studies showed the crosslink between signaling pathways of inflammation and insulin resistance. For example, attenuated TNF‐α and TNF‐α receptor, and JNK signaling in high‐fat diet‐treated mice could reduce inflammation markers and blood sugar levels (Uysal, Wiesbrock, Marino, & Hotamisligil, 1997), and elevated the sensitivity of insulin signaling pathway (Hotamisligil, 1999; Nieto‐Vazquez et al., 2008). Therefore, reduction in inflammation by inhibiting proinflammatory cytokine production would be an alternative way to improve the insulin sensitivity of adipocytes and induce the cellular glucose uptake.…”

Metagenomic study of single-nucleotide polymorphism within candidate genes associated with type 2 diabetes in

“…In this study, 5 prominent mutations spanning across 4 genes were investigated for their link with diabetic condition in an Indian resource population. The genes include the ligand inducible transcription factor-coding vitamin D receptor (VDR) gene (Ogunkolade et al, 2002), interleukin-6 (IL-6) gene (Vozarova et al, 2001), tumor necrosis factor-alpha (TNF-α) gene (Hotamisligil, 1999), and transcription factor 7-like 2 (TCF7L2) gene, a member of the T-cell-specific high-mobility group boxcontaining family of transcription factors (da Silva et al, 2009). …”

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

“…Tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) are cytokines secreted from adipose tissue as adipokines as well as from other tissues 8. Both have important roles in the induction of insulin resistance in NAFLD and type II diabetes,8, 13, 14 and iron has been shown in cell culture studies to promote a proinflammatory phenotype in macrophages 15…”