Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects

Abstract

Aims/hypothesis Obesity is associated with insulin resistance and inflammation. The circulating human mononuclear cell (MNC) has been shown to respond to low-dose insulin infusion. We have now investigated whether in obesity: (1) phosphorylated insulin receptor beta subunit (p-INSR-β) is reduced in the MNC; (2) pro-inflammatory mediators including inhibitor of kappa light polypeptide gene enhancer in B cells-kinase beta (IKBKB), suppressor of cytokine signalling-3 (SOCS) and protein kinase C-beta 2 (PRKCB2) are increased and related to p-INSR-β; and (3) the reduction in MNC p-INSR-β is related to the reduction in insulin sensitivity. Materials and methods MNCs were prepared from fasting blood samples of 16 normal weight and 16 obese female subjects. Results Our data show that p-INSR-β is reduced significantly in MNCs from obese subjects compared with that of normal controls. MNCs from obese subjects have higher IKBKB expression, increased nuclear factor kappa B (NFκB) binding and higher mRNA expression of TNFAIP1 and IL6 genes. NFκB binding, TNFAIP1 mRNA and plasma C-reactive protein are inversely related to p-INSR-β. PRKCB2 mRNA and protein expression were significantly higher in the obese subjects and were related significantly to pro-inflammatory mediators but not to p-INSR-β. SOCS3 mRNA expression was markedly elevated and positively related to proinflammatory mediators including IKBKB and PRKCB2 on the one hand and inversely related to p-INSR-β on the other. Conclusions/interpretation We conclude that in obesity the MNC is characterised by reduced p-INSR-β and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-β and might mediate the inhibition of p-INSR-β. These data elucidate the relationship between inflammation and insulin resistance using the MNC as a model.

Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

“…Moreover, the decrease in IL1B mRNA expression was associated with an improvement of insulin and glucose metabolism [9]. These findings and those of others suggest that these cells are a target for insulin action and can be used as a model to study inflammation and its relationship with insulin resistance [12][13][14]. Moreover, monocytes, which along with lymphocytes, are an important cell type in PBMCs, differentiate into macrophages in most tissues [15], including adipose tissue.…”

“…The fact that the decrease in IKBKB expression was generally highly associated with these markers supports our supposition. Indeed, in humans, obesity is associated with increased NFκB binding activity and IKBKB expression in circulating mononuclear cells [12,13]. Macrophage infiltration in adipose tissue has been linked to obesity-related inflammation and insulin resistance [33,34], and upregulation of CCL5 in visceral fat of obese individuals with the metabolic syndrome has recently been associated with markers of T cells and macrophages in this tissue [35].…”

Macronutrient intake induces oxidative and inflammatory stress: potential relevance to atherosclerosis and insulin resistance

“…In addition, type 2 diabetes is also known to be associated with chronic inflammation (Pickup et al, 1997). Recent data also demonstrate that inflammatory mediators may interfere with insulin signal transduction (Hotamisligil et al, 1996;Ghanim et al, 2007a). These facts reinforce the importance of inflammation in the pathogenesis of insulin resistance and type 2 diabetes.…”

The expression of genes involved in NF-κB activation in peripheral blood mononuclear cells of patients with gestational diabetes

“…study the relationship between low-grade inflammation and insulin resistance (10,11,22,23,24). As such studies have never been carried out in patients with gestational diabetes (GDM), we hypothesized that the development of insulin resistance and hyperglycemia during pregnancy may influence the expression of genes encoding receptors of surface ligands and immune mediators involved in NF-kB signaling pathway.…”