Insulin binding to fat and blood cells and the effect of insulin on glucose transport, glucose oxidation, lipogenesis, and lipolysis in fat cells were measured in 23 conventionally treated insulin-dependent diabetics (IDDs) with a mean duration of diabetes for 10 yr. In the fasting state diabetics had increased plasma levels of free insulin (P < 0.001) accompanied by a 38% reduction of insulin binding to fat cells (P < 0.001), whereas insulin binding to monocytes and erythrocytes was normal. The concentrations of insulin causing halfmaximal effect on glucose transport and antilipolysis in adipocytes were both higher in diabetics than in normals (P < 0.001), suggesting impaired sensitivity to insulin that may be the functional consequence of the adipocyte insulin receptor defect. The basal rates and the maximal responses to insulin of glucose transport and lipolysis were both within the limits of normals, indicating the absence of postreceptor abnormalities in these effector systems. In contrast, both glucose oxidation and lipogenesis in fat cells from diabetics had normal sensitivity to insulin. This finding was very surprising and suggests possible postreceptor modulation o the insulin sensitivity of glucose metabolism in insulin-treated diabetics counterbalancing the effects of decreased insulin receptor binding. Moreover, both the basal rates for glucose oxidation and lipogenesis and the absolute response of glucose oxidation and lipogenesis rates to maximal insulin stimulation were significantly reduced in fat cells from diabetics indicating postreceptor impairments of glucose metabolism. In conclusion: In long-term-treated IDDs in usual metabolic control and with fasting, peripheral hyperinsulinemia insulin binding to circulating blood cells was normal. In contrast, a peripheral, fixed tissue, as fat cells, exhibited decreased insulin bindingwith impaired insulin sensitivity of some pathways (glucose transport and antilipolysis) and postreceptor impairments of other pathways (lipogenesis and glucose oxidation).