Glucose intolerance, due to insulin resistance, is a major feature of diabetes mellitus and many other chronic diseases and also a determinant of morbidity and mortality. The exact pathofysiology of insulin resistance is not known. An important role has been ascribed to fatty acids. The research of the Metabolic Group AMC is dedicated to unraveling in chronically ill patients the pathofysiology of the disturbances in glucose and fat metabolism, and its interaction, with emphasis on diabetes mellitus. The models chosen have either the characteristic of increased insulin resistance or increased insulin sensitivity. The major research tool is the application of stable isotopes. With this tool kinetic exploration of the biochemical pathways in vivo is feasible. The studies are done in premature infants, children and adults. Studies are also performed in patients with HIV-infection, septic patients, surgical patients, patients with malaria, patients with Gaucher disease and patients with type 2 diabetes mellitus. The role of different mediators as TNF-a, interferon-a, interferon-g and interleukin-6 has been explored in healthy subjects. Recently molecular biological and biochemical methods have been added to the stable isotope methods to create a combined approach for resolving the research questions.