Fructose raises blood glucose and lactate levels in normal as well as diabetic man, but the tissue origin (liver and/or kidney) of these responses and the role of insulin in determining the end products of fructose metabolism have not been fully established. Splanchnic and renal substrate exchange was therefore examined during intravenous infusion of fructose or saline in six insulin-deficient type I diabetics who fasted overnight and in five healthy controls. Fructose infusion resulted in similar arterial concentrations and regional uptake of fructose in the two groups. Splanchnic glucose output increased threefold in the diabetics but remained unchanged in controls in response to fructose infusion, and the arterial glucose concentration rose more in diabetics (+5.5 mmol/liter) than in controls (+0.5 mmol/liter). Splanchnic uptake of both lactate and pyruvate increased twofold in response to fructose infusion in the diabetics. In contrast, a consistent splanchnic release of both lactate and pyruvate was seen during fructose infusion in controls. In diabetics fructose-induced hyperglycemia was associated with no net renal glucose exchange, while there was a significant renal glucose production during fructose infusion in the controls. In both groups fructose infusion resulted in renal output of lactate and pyruvate. In the diabetics this release corresponded to the augmented uptake by splanchnic tissues. In two diabetic patients given insulin infusion, all responses to fructose infusion were normalized. Fructose infusion in diabetics did not influence either splanchnic ketone body production or its relationship to splanchnic FFA inflow. We conclude that in insulin-deficient, mildly ketotic type I diabetes, (a) both the liver, by virtue of lactate, pyruvate, and fructose-derived gluconeogenesis, and the kidneys , by virtue of fructose-derived lactate and pyruvate production, contribute to fructose-induced hyperglycemia; (b) outcome of hepatic fructose metabolism; and (c) fructose does not exert an antiketogenic effect. These data suggest that while total fructose metabolism is not altered in diabetics, intermediary hepatic fructose metabolism is dependent on the presence of insulin.