Increasing the blood glucose levels from 88 to 400 mg/IOO ml in rabbit liver in situ during 5-min time intervals resulted in a decrease in the production of C02 from C-I of liver glucose together with a slight increase in the oxidation of C-6 of glucose; this was caused by a high glucose-induced decrease in the activity of the oxidative pentose phosphate pathway. Increasing the glucose concentrations also resulted in a threefold increase in the levels of palmitoyl-and stearoyl-CoA esters at a glucose load of 0·8 g; this is consistent with a specific feed-back inhibition of the production of NADPH by reactions of the oxidative pentose phosphate pathway by long-chain fatty acyl-CoAs. A decrease in plasma free fatty acids occurred when blood glucose levels were raised; this was associated with an increase in the concentration of free fatty acids in liver.There was a decreased glucose output by liver following an increased glucose load. In liver there were increases in AMP levels, decreased ATP levels, a twofold increase in fructose 1,6-diphosphate and a fall in glucose 6-phosphate and fructose 6-phosphate concentrations. These changes are indicative of the decreased gluconeogenic flux caused through inhibition of hexosediphosphatase by AMP, and the elevated levels of the long-chain fatty acyl-CoA esters probably acted to inhibit adenine nucleotide translocation across the mitochondrial membrane. The formation of sn-glycero-3-phosphate appears to be the rate-limiting step for relieving the inhibitions caused by the accumulation of long-chain fatty acyl-CoAs.

Studies of the transient changes in the maximum catalytic capacities of glucose-metabolizing enzymes in preneoplastic rat liver revealed significant decreases in the activities of only two enzymes, glucokinase and hexosediphosphatase. The activities of hexokinase, glucose-6-phosphate dehydrogenase, and phosphogluconate dehydrogenase increased threefold and there was a significant elevation of liver enzymes in the serum after 45 days of carcinogen treatment.Fluctuations in the in vivo concentrations of glycolytic intermediates reflected an increased glycolytic flux with an activation of the lower segment of the pathway at the pyruvate kinase level. The constancy of the mass action ratios for the glycolytic reactions suggested that there was no impairment of the regulatory status of glycolysis in the preneoplastic period. There was, however, a most notable metabolic impairment in the disruption of the interrelationship between the phosphorylation potential and the cytoplasmic pyridine nucleotide ratio.