Arterial concentrations and splanchnic exchange of glucose, lactate, pyruvate, glycerol, free fatty acids, and individual acidic and neutral amino acids were determined in obese and nonobese control subjects in the basal state and during a 45 min infusion of glucose. Glucose was administered to the controls at a rate (2 mg/kg/min; 144 +/- 4 mg/min) known to inhibit splanchnic glucose output without influencing peripheral glucose utilization. The obese subjects received glucose at two dose levels (75 and 150 mg/min) which simulated either the rise in insulin or the inhibition in splanchnic glucose production observed in the controls. In the basal state splanchnic glucose production did not differ significantly between obese and control subjects. However splanchnic uptake of lactate, glycerol, alanine, free fatty acids, and oxygen was 50-160% greater in obese subjects. Splanchnic uptake of glucose precursors could account for 33% of hepatic glucose output in the obese group as compared to 19% in controls. The increase in alanine and lactate uptake was due in part, to a 50% increase in splanchnic fractional extraction. Administration of glucose to the control subjects 144 +/- 4 mg/min) resulted in a 50-60% increment in arterial insulin and a 75% reduction in splanchnic glucose output. In the obese group, infusion of glucose at a rate of 75 mg/min resulted in an equivalent rise in arterial insulin, but was accompanied by a less than 40% inhibition in splanchnic glucose output. Glucose infusion at a rate of 150 mg/min in the obese resulted in a 75% reduction in splanchnic glucose output which was equivalent to that observed in controls, but was accompanied by a significantly greater rise (100-200%) in arterial insulin. It is concluded that in obesity (a) despite basal hyperinsulinemia, splanchnic uptake of glucose precursors is increased, the relative contribution to total glucose release attributable to gluconeogenesis being 70% higher than in controls; (b) infusion of glucose at rates causing equivalent increases in arterial insulin induces a smaller inhibition in splanchnic glucose output than in controls; (c) infusion of glucose at rates causing comparable inhibition in splanchnic glucose output is accompanied by a disproportionately greater increase in endogenous insulin than in controls. These data are compatible with hepatic resistance to insulin in obesity.