Previously, we have shown increased IL-1 secretion from Type 2 diabetic patients compared to controls. We therefore aimed to delineate the mechanism of IL-1 induction under high glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentration of D-glucose (10-25 mM) for 6-72hr. IL-1 and IL-1ra levels were measured using ELISA and Western blots, while mRNA was quantitated by RT-PCR. Specific inhibitors and siRNAs of PKC, p38, ERK1/2, NF-B, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1 secreted protein, cellular protein, and mRNA increase under high glucose conditions is time and dose dependent with maximum increase at 15mM (48hr, p<0.05). IL-1ra release was time and dose dependent similar to IL-1 expression pattern, however, the molar ratio of IL-1/IL-1RA was increased. Data from inhibitor and siRNA experiments indicate that IL-1 release under HG is mediated by PKC- , via phosphorylation of p38MAPK, ERK1/2 leading to NF-B activation, resulting in increased mRNA and protein for IL-1. At the same time, it appears that NADPH oxidase via p47phox activates NF-B resulting in increased IL-1 secretion. Data suggests that under high glucose conditions, monocytes release significantly higher amounts of IL-1 through multiple mechanisms further compounding the disease progression. Targeting signaling pathways mediating IL-1 release could result in the amelioration of inflammation and possibly diabetic vasculopathies.