The mechanism by which type 2 diabetes dramatically increases atherosclerotic risk remains poorly understood. Type 2 diabetes is preceeded by long periods of insulin resistance and associated abnormalities such as, high serum free fatty acid (FFA) levels, hyperinsulinemia, hyperglycaemia and obesity, collectively described as 'syndrome X'. Due to the fact that atherosclerosis is generally observed at the time of diagnosis of diabetes it is thought that syndrome X could be the cause of increased atherogenesis. Accumulation of cholesterol esters (CE) in macrophage foam cells is an important early event in atherosclerosis. The neutral cholesterol esterase responsible for the hydrolysis of CEs in macrophages is identical to hormone-sensitive lipase (HSL) in adipocytes. In adipocytes insulin exerts an anti-lipolytic function by decreasing HSL activity, suggesting that insulin may also regulate HSL in macrophages. Therefore the regulation of HSL in macrophages has been studied and compared to that in adipocytes. HSL activity is acutely downregulated by insulin, as it is in adipocytes. However this acute effect of insulin on HSL in macrophages does not appear to be dependent on PI 3-kinase activity, as it is in adipocytes. Leptin is a hormone, produced in adipocytes, that is raised in the circulation of obese individuals and this hormone was found to acutely increase HSL activity in macrophages. The regulation of HSL activity by leptin is blocked by wortmannin, suggesting that PI 3-kinase is involved. HSL expression and activity were increased in adipocytes upon chronic stimulation with insulin under high glucose conditions but activity and expression were decreased in macrophages. Chronic incubation with leptin and high glucose also caused a reduction in HSL expression and activity in macrophages. Insulin and leptin in combination with high glucose also caused an increase in CE accumulation. Therefore a mechanism linking hyperinsulinemia, hyperglycaemia and obesity to foam cell formation and increased atherogenesis has been identified.