Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus

Resistin is an adipokine that promotes inflammation and insulin resistance by targeting several cells including platelets. We hypothesised that in type 2 diabetes (T2DM), resistin may foster in vivo oxidative stress, thromboxane-dependent platelet activation and platelet-derived inflammatory proteins release, key determinants of atherothrombosis. A cross-sectional comparison of circulating resistin, sCD40L, as a marker of platelet-mediated inflammation, asymmetric dimethylarginine (ADMA), endothelial dysfunction marker, Dickkopf (DKK)-1, reflecting the inflammatory interaction between platelets and endothelial cells, and urinary 8-iso-PGF(2 alpha) and 11-dehydro-TxB(2), reflecting in vivo lipid peroxidation and platelet activation, respectively, was performed between 79 T2DM patients and 30 healthy subjects. Furthermore, we investigated the effects of the alpha-glucosidase inhibitor acarbose and the PPAR. agonist rosiglitazone, targeting hyperglycaemia or insulin resistance, versus placebo, in 28 and 18 T2DM subjects, respectively. Age-and gender-adjusted serum resistin levels were significantly higher in patients than in controls. HOMA (beta= 0.266, p= 0.017) and 11-dehydro-TXB2 (beta= 0.354, p= 0.002) independently predicted resistin levels. A 20-week treatment with acarbose was associated with significant reductions (p= 0.001) in serum resistin, DKK-1, urinary 11-dehydroTXB(2) and 8-iso-PGF(2 alpha) with direct correlations between the change in serum resistin and in other variables. A 24-week rosiglitazone treatment on top of metformin was associated with significant decreases in resistin, DKK-1, 11-dehydro-TXB2 and 8-iso-PGF(2 alpha), in parallel with HOMA decrease. In conclusion, resistin, antagonising insulin action in part through PPAR. activation, may favour insulin resistance and enhance oxidative stress, endothelial dysfunction and platelet activation. The adipokine-platelet interactions may be involved in platelet insulin resistance and their consequent pro-aggregatory phenotype in this setting.