Molecular interactions between inflammation and insulin resistance in obesity

Insulin resistance, which is a state of subnormal biological response to insulin, is closely associated with type 2 diabetes. Obesity, a state of low grade chronic inflammation, is also closely associated with insulin resistance and is a major risk factor for type 2 diabetes. Previous reports suggest a role for inflammation in the development of insulin resistance in cell lines and animal models. Although the association between obesity and insulin resistance is strong, the role of inflammation has not been fully in humans and the molecular mechanisms of this role are not clearly described. Therefore, we plan to investigate the possible role of inflammatory mediators in developing insulin resistance in obesity in human subjects and the cellular pathways involved, using the mononuclear cells (MNC) as a model to investigate this hypothesis.; Fasting blood samples were collected from age and gender matched obese and lean subjects. Circulating MNC were isolated and RNA, nuclear extracts and total cell homogenate were prepared. The data demonstrate that the MNC in obesity is in a proinflammatory state indicated by increased NFkappaB DNA binding and increased expression of proinflammatory cytokines and markers such as TNF-alpha, IL-6, MIT and MMP-9 expression. The inflammatory mediators in the MNC and in circulation correlate significantly with BMI and HOMA-IR, an index of insulin resistance. Obesity was also associated with significantly lower IR tyrosine phosphorylation, the first step in insulin signaling transduction. Furthermore, there is significant inverse correlation between IR phosphorylation, on one hand, and inflammatory mediator's levels and HOMA-IR on the other.; The proinflammatory and insulin resistant state of the MNC in obese is associated with increased expression of PPARgamma, a nuclear transcription factor involved in lipid and glucose homeostasis. Role of PPARgamma in this association between inflammatory mediators and insulin resistance was further tested by treating obese subjects with troglitazone, an insulin sensitizer and a PPARgamma ligand. The treatment improved insulin sensitivity, reduced inflammation and at the same time reduced PPARgamma expression indicating that PPARgamma might a common modulator of the inflammatory and insulin signaling pathways.; We finally investigated possible mechanisms by which inflammatory mediators can directly interfere with insulin signaling at the receptor level. Obesity was associated with increased expression of SOCS-3 and PKC-betaII in the MNC. (Abstract shortened by UMI.)...