This study evaluated the potential contribution of the liver to glucose intolerance and insulin resistance in acute uremia. Eight bilaterally nephrectomized dogs and eight sham-operated dogs were studied, while awake, 24 to 30 hours after surgery. Blood levels and hepatic balance of glucose, lactate, and amino acids were measured during a baseline period and during a 90-minute infusion of glucose and insulin that maintained plasma glucose at 9 to 10 mmol/L. During the basal state, the acutely uremic dogs, in comparison to control dogs, displayed decreased femoral artery plasma glucose, whole blood total amino acids, and elevated blood lactate. In the liver of the uremic dogs, there was lower glucose output, less uptake of alanine, greater uptake of glutamine, and similar uptake of lactate, as compared with controls during the basal state. In the control dogs during the hyperglycemic clamp, the liver took up glucose and released lactate; the hepatic uptake of alanine diminished, and the hepatic output of glutamine persisted. In contrast, during the hyperglycemic clamp in the uremic dogs, there was no hepatic uptake of glucose; the hepatic uptake of alanine, glutamine, and lactate persisted, and the hepatic uptake of total amino acids was greater than in controls. Peripheral glucose uptake was also impaired in the acutely uremic dogs. Moreover, the uremic dogs had insulin resistance, as indicated by a low ratio of the glucose infusion rate to the plasma insulin levels, and a higher urea nitrogen appearance. Thus, acutely uremic dogs have altered hepatic handling of glucose and its precursors, which only becomes evident during a glucose load.(ABSTRACT TRUNCATED AT 250 WORDS)