The present study was performed to determine whether insulin resistance, independent of the prevailing hormonal milieu, occurs in the liver during sepsis. To determine this, sepsis was produced in rats by cecal ligation and puncture (CLP). Six hours later, when the rats were in the early hypermetabolic phase of sepsis, the livers were isolated and perfused with Krebs-HCO3buffer using a nonrecirculating system. The effects of various concentrations of insulin on the gluconeogenic response to lactate and phenylephrine stimulation were determined. In the absence of insulin and phenylephrine, there was no difference in the rates of glucose production from lactate between septic and sham-operated rats. The gluconeogenic response to phenylephrine stimulation was, however, significantly depressed in the livers from septic rats. Addition of 50 jiU insulin/ml resulted in an inhibition of the phenylephrine-stimulated glucose release from livers from sham-operated rats. © 1984 by The Williams & Wilkins Co.