Glucose reduces the hepatic conversion of aminonitrogen to urea, quantified by the functional hepatic nitrogen clearance (i.e., the slope of the linear relation between urea synthesis rate and blood α-aminonitrogen concentration). This is due to a direct effect of glucose and to inhibition of glucagon. In this study, the effect of glucose on functional hepatic nitrogen clearance was examined during spontaneous hormone responses and during hormonal control by somatostatin. In 7 control subjects (study 1) and 9 patients with cirrhosis (study 2), functional hepatic nitrogen clearance was assessed twice in each subject: during infusion of alanine and during alanine administration superimposed on a continuous glucose infusion (blood glucose, on average = 8.4 mmol/L). In study 3, 6 patients with cirrhosis had functional hepatic nitrogen clearance determined on three occasions: during infusions of alanine and of alanine superimposed on infusion of somatostatin with either euglycemia or hyperglycemia (blood glucose = 8.4 mmol/L). In the control subjects (study 1), functional hepatic nitrogen clearance was 32.5 ± 1.9 L/hr, and glucose reduced it to 18.4 ± 0.9 L/hr (p < 0.01). In the cirrhotic patients, functional hepatic nitrogen clearance was only 9.8 ± 1.3 L/hr (p < 0.01 vs. controls), and glucose did not change it. In the control subjects, glucose reduced the glucagon response to alanine from 204 ± 36 ng/L to 106 ± 8 ng/L (p < 0.05). In the cirrhotic patients the mean fasting glucagon level was increased twofold (180 ± 21 ng/L). The response to alanine increased to 968 ± 265 ng/L; it was not reduced by glucose. In study 3, somatostatin and hyperglycemia reduced functional hepatic nitrogen clearance from 13.2 ± 1.5 L/hr to 6.4 ± 0.7 L/hr (p < 0.01). Somatostatin and euglycemia reduced functional hepatic nitrogen clearance to 9.2 ± 1.2 L/hr (p < 0.01 vs. alanine and hyperglycemia). The results show that the reduction by glucose of hepatic aminonitrogen conversion is lost in cirrhotic patients. The markedly increased glucagon response to alanine was not suppressed by glucose. Inhibition of the glucagon response by somatostatin reestablished the glucose effect, which was in part due to inhibition of glucagon in itself. Thus hepatic aminonitrogen conversion in cirrhosis depends on increased glucagon levels. The hormone-independent effect of glucose is preserved if the hyperglucagonemia is abolished, but the spontaneous high glucagon level overrules the glucose effect. The results indicate reduced hepatic contribution to the nitrogen-sparing effect of glucose in cirrhotic patients. (Hepatology 1994;19:45–54).