Introduction: Insulin resistance states are increasing in the developed world at alarming rates with recent studies suggesting that between 12% and 25% of the population are affected. Albuminuria is the earliest sign that the kidney is affected in these conditions. The podocyte is critical for preventing albumin loss into the urine and we have recently shown this cell is insulin sensitive cell with kinetics similar to that of muscle (1). Interleukin-6 (IL-6) is shown to be elevated in the insulin resistant metabolic syndrome. We have studied the effects of co-incubating podocytes with IL-6 on the insulin responsiveness of this cell and it’s affect on the know insulin signalling pathways described in insulin responsive cells (PI3-kinase and MAP-kinase phosphorylation). Methods: Conditionally immortalised human podocytes were either grown in standard culture conditions with or without high physiological doses of IL-6, TNF-alpha or both (100pg/ml). Cells were then starved of insulin for 12 hours and 2-Deoxyglucose uptake assays performed to assess insulin responsiveness (15 minutes 100nM) in respect to glucose uptake. Insulin signalling was also assessed using Western blotting with phosphospecific antibodies to assess activation of the PI3-kinase and MAP-kinase pathways. Results: Co-incubating podocytes with IL-6 abrogates the glucose uptake response completely (p<0.05). Interestingly IL-6 does not affect insulin stimulated PI3-kinase or MAPK pathways, upstream of Akt (PKB) or p44/42 MAPK. In IL-6 treated podocytes phospho-Akt [Ser473] (p<0.05) increased by 90% in response to 5 minutes exposure to 100nM insulin (p<0.05) and p44/42 MAP Kinase increased by 108% (p<0.05) under the same conditions. We have also shown that insulin stimulated glucose uptake in the cells is dependent on intact PI3-kinase and MAP-kinase pathways by the use of LY294002 and UO126 inhibitors, (inhibition of either pathway completely abrogates glucose uptake). Statistical analysis was performed using ANOVA with post hoc Bon Ferroni, with between 3-6 independent experiments carried out for each result. Conclusions: IL-6 directly induces insulin resistance in human podocytes. Mechanistically its effect is not through inhibition of proximal PI3-kinase or MAP-kinase pathways which are critical for podocyte insulin signalling. We conclude that IL-6 is having its effect either through the distal parts of these pathways or through another signalling pathway. Understanding the mechanism by which IL-6 renders the podocyte insulin resistant may lead to new therapeutic targets in insulin resistant states.