Previous studies on the relationship between insulin resistance and obesity have demonstrated the advantages of weight loss and the disadvantages of weight gain. It is possible, however, that the overnutrition which preceeds obesity may be more important than the obese state for the development of insulin resistance. We have examined the effect of overnutrition on the development of insulin resistance in subjects with normal glucose tolerance. Insulin resistance in the periphery and the liver was assessed with the euglycemic clamp at 100 and 1800 MuU/ml insulin using 3H-glucose to measure hepatic glucose production. Changes in glucose storage and oxidation were measured in vivo using indirect calorimetry. The results of this preliminary study indicate the importance of acute overnutrition for the development of insulin resistance. In addition, it relates overnutrition induced changes in glucose disposal rates to in vivo measurements of non-oxidative glucose disposal rates determined by indirect calorimetry.