Glucose metabolism and insulin sensitivity of isolated rat epididymal fat cells and of their delipidated derivatives ("ghosts") was studied as a function of cellular lipid content (fat cell size), cellular protein content, animal age, and state of nutrition in an effort to examine the relationship of adipose cell size to adipose tissue insulin sensitivity.In ad libitum-fed rats, basal rates of glucose-1-(14)C incorporation into CO(2) and triglyceride are similar over a wide range of adipose cell size. In contrast, the insulin sensitivity of intact fat cells from rats fed ad libitum is inversely related to their lipid content: the larger the cell, the less the response to insulin. This "resistance" of the enlarged adipose cell to the action of insulin was demonstrated by a reduction in the per cent rise above the basal rate as well as in the absolute rate of glucose oxidation and lipogenesis caused by insulin. The protein content of fat cells was found to be relatively constant over a wide range of fat cell size. Thus, enlarged insulin "resistant" fat cells contained the same amount of protein as smaller insulin "sensitive" cells. These relationships between insulin sensitivity and cellular lipid or protein content were true regardless of whether cells of different sizes were obtained from animals of different body weights and ages, or from different portions of the epididymal fat pads of animals of the same weight and age.Acute delipidation of intact fat cells did not appear to alter these relationships between basal glucose metabolism, insulin sensitivity, and cell size. "Ghosts" prepared from fat cells of widely different sizes metabolized glucose to CO(2) and triglyceride at similar rates. The insulin sensitivity of the fat cell "ghost" appeared to be inversely related to the size of the intact cell from which it was derived: the larger the intact cell the less insulin sensitive its "ghost."Although the insulin "resistance" of adipose tissue was reversed by weight loss and reduction of fat cell size, these studies also demonstrate that the insulin sensitivity of adipose cells of similar sizes can vary widely depending upon the state of nutrition and growth of the animal. Thus, factors other than cell size can also influence the insulin sensitivity of the adipose tissue.