DECREASED HEPATIC GLUCOSE-PRODUCTION IN RATS WITH CARBON TETRACHLORIDE-INDUCED CIRRHOSIS

Energy metabolism was studied in fed and fasted rats with carbon tetrachloride (CCl4)-induced cirrhosis. In situ liver perfusion experiments were performed under basal conditions (no substrate added to the perfusate) and after stimulation with glucagon (2 nM) and L-alanine (20 mM). Under basal conditions, oxygen consumption per gram of liver was reduced in cirrhotic rats irrespective of the metabolic state. After addition of glucagon/L-alanine to the perfusate, oxygen consumption increased significantly in fed and fasted control and cirrhotic rats. Under basal conditions, glucose production was reduced by 76% in cirrhotic rats, averaging 0.75 +/- 0.19 vs. 0.18 +/- 0.15 mumol.g liver-1.min-1 in control and cirrhotic livers, respectively (means +/- S.E.M., P < 0.05). After addition of glucagon/L-alanine to the perfusate, glucose production increased in both groups and was reduced by 65% in fed cirrhotic as compared with fed control rats, averaging 3.63 +/- 0.27 vs. 1.27 +/- 0.17 mumol.g liver-1.min-1 in control and cirrhotic rats, respectively (P < 0.05). Stimulated glucose production was linearly correlated with the fractional aminopyrine elimination rate constant (ABT-k), a measure of hepatic function in vivo. After 12 h of fasting, stimulated glucose production was decreased by 15% in control and by 65% in fed cirrhotic rats compared with the fed state, averaging 3.07 +/- 0.22 vs. 0.33 +/- 0.03 mumol.g liver-1.min-1 in control and cirrhotic rats, respectively (P < 0.05). After 24 h of starvation, glucose production was not significantly different between control and cirrhotic rats. In contrast to glucose production, rates of urea, lactate or pyruvate production were not significantly different between cirrhotic and control rats in the fed state. Thus, in the fed state, hepatic glucose production is reduced in cirrhotic rats both under basal conditions and after stimulation with glucagon/L-alanine. The reduction in hepatic glucose production in the fed state may be a result of decreased glycogenolysis and may explain decreased glucose production in patients with cirrhosis following glucagon administration.