Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors).