We studied insulin binding, receptor autophosphorylation, and insulin action in isolated adipocytes from 23 Pima Indians with varying degrees of obesity over a range of glucose tolerance. [125I]Insulin binding varied widely and did not correlate with fasting plasma immunoreactive insulin levels or insulin sensitivity, as assessed by the ED50 values of insulin stimulation of glucose transport or insulin inhibition of lipolysis in isolated abdominal wall adipocytes obtained by biopsy from the patients. In contrast there was a significant correlation between loss of stimulation of autophosphorylation in solubilized receptors and loss of insulin sensitivity for both stimulation of glucose transport (r = -0.59; P less than 0.005) and inhibition of lipolysis (r = -0.54; P less than 0.01). There was also a significant inverse correlation between insulin's ability to stimulate receptor autophosphorylation and in vivo insulin resistance, as assessed by fasting plasma insulin levels (r = -0.46; P less than 0.05). These data indicate a significant correlation between changes in sensitivity of glucose transport and antilipolysis to insulin and receptor kinase activity in those patients and suggest that defective coupling of insulin binding to insulin action at the level of phosphorylation of the insulin receptor may cause the insulin resistance in this group of patients.