The relation of urea synthesis rate to blood alanine concentration was assessed in seven healthy controls and eight patients with non-insulin-dependent diabetes mellitus (NIDDM) before (hemoglobin A1c [HbA1c] = 9.9% +/- 1.9%, mean +/- SD) and after (HbA1c = 7.9% +/- 0.8%) improvement of metabolic control. Following an overnight fast, alanine was infused at a rate of 2 mmol/(h.kg body weight [BW]). The hourly rate of urea synthesis was determined as the urinary excretion of urea corrected for accumulation of urea in total body water (TBW) and intestinal hydrolysis. The functional hepatic nitrogen clearance (FHNC) was calculated as the slope of the linear relation of urea synthesis rate to blood alanine concentration. The glucagon level was increased by twofold at the first investigation, but was not increased at the second. The insulin level was moderately increased at both investigations. In controls FHNC was 21.8 +/- 4.4 L/h, in poorly controlled patients it was increased to 36.6 +/- 4.3 L/h (P < .01), and following improvement of metabolic control it was not different from control levels at 28.6 +/- 4.3 L/h. By correlation analyses, FHNC was found only to be related to the fasting glucose value, albeit weakly (R2 = .39). In conclusion, hepatic kinetics of urea synthesis in poorly controlled NIDDM patients are changed in favor of increased conversion of alanine N to urea N at any amino acid concentration. This perturbation is partially normalized by improved metabolic control.