Intraperitoneal infusion of insulin should be more physiological than intravenous insulin since part of the insulin is directed toward the portal vein, which allows the liver to retain its major role in glucose homeostasis. The regulation of hepatic glucose production during the intraperitoneal and intravenous infusions of insulin were compared in eight Type 1 (insulin-dependent), C-peptide-deficient diabetic patients. Primed, continuous infusions of [6,6-2H]glucose were given in the postabsorptive state and during continuous infusion of unlabelled glucose at 1.5 and 4 mg/kg.min, while normoglycaemia was maintained by closed-loop intraperitoneal and intravenous insulin delivery. During all three periods, plasma glucose concentrations remained near normal (variations 3.8-6.1%). The insulin infusion rates required for normal plasma glucose concentrations were essentially the same for the intravenous and intraperitoneal routes in all cases, although the variations were greater with intraperitoneal insulin. Plasma free-insulin levels were only slightly, non-significantly lower with intraperitoneal infusion than with intravenous infusion. Hepatic glucose production was significantly lower with intraperitoneal insulin during all three conditions: basal: 1.71 +/- 0.14, i.p. vs 2.37 +/- 0.26 mg/kg.min, i.v.; 1.5 mg/kg.min glucose infusion: 0.49 +/- 0.23, i.p. vs 0.88 +/- 0.18 mg/kg.min, i.v.; 4 mg/kg.min glucose infusion: 0.31 +/- 0.10, i.p. vs 0.56 +/- 0.12 mg/kg.min, i.v.. These results, obtained with steady-state conditions for plasma glucose, isotopic plasma glucose enrichments and unlabelled glucose infusion rates, suggest that better control of hepatic glucose production leading to normoglycaemia was achieved with the intraperitoneal infusion.