Search

Glucose utilization and production by the isolated perfused rat liver have been examined under a variety of conditions. Rat livers perfused with 20 m m lactate and increasing glucose concentrations from 3 to 55 m m come to a point of equilibrium at which glucose production equals glucose utilization. This occurs with an initial glucose concentration of about 12 m m in the normal fasted rat and 20 m m in the alloxan diabetic. An increase in glucose utilization was observed in livers from diabetic rats with initial perfusate glucose concentrations greater than 30 m m . Such a response is not consistent with the properties of any of the known enzyme systems that convert glucose to glucose-6-phosphate. Further, it has been observed that in prolonged fasting glucose utilization is not depressed to the extent that glucokinase activity is decreased. Although glucose utilization by the normal rat liver would appear to be regulated by glucokinase, alterations observed in alloxan diabetes and prolonged fasting are not consistent with phosphorylation by this enzyme.

4-Pentenoic acid has been shown to have a hypoglycemic effect on mice in vivo (1) and to inhibit gluconeogenesis and lactate oxidation in pigeon liver homogenates (2). Gluconeogenesis from alanine or pyruvate is inhibited by 4-pentenoic acid in perfused rat liver (3,4), and glucose production from pyruvate and succinate is decreased in rat kidney slices (5). 4-Pentenoic acid also inhibits the oxidation of fatty acids in a variety of systems (1–8). Since fatty acids are known to stimulate glucose production by the liver (9, 10), the impairment of gluconeogenesis has been attributed to a suppression of fatty acid oxidation. It has been suggested that inhibition of fatty acid oxidation is mediated by lack of free CoA and carnitine as a result of the accumulation of non-metabolizable CoA and carnitine esters formed during the oxidation of 4-pentenoic acid (2,6). However, no detailed studies on possible changes of CoA intermediates in tissues have been reported. In the present work, the kinetics of the effects of 4-pentenoic acid on adenine and pyridine nucleotides, CoA and carnitine derivatives have been determined in the perfused rat liver. These studies, and data obtained with intact and sonicated mitochondria show that the metabolic deficiencies observed in liver are caused both by inhibition of β-oxidation, and by depletion of CoA and acetyl-CoA.