Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart

Abstract

The concentrations of glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-diphosphate were determined in extracts of perfused rat heart, and the effects of alloxan-diabetes and starvation, and of anoxia, salicylate, 2,4-dinitrophenol, fatty acids and ketone bodies, were investigated. Anoxia, salicylate and 2,4-dinitrophenol decreased the concentrations of glucose 6-phosphate and fructose 6-phosphate, but increased that of fructose 1,6-diphosphate. These changes have been interpreted as indicating specifically acceleration of the phosphofructo-kinase reaction. In hearts from alloxan-diabetic or starved rats the concentrations of the hexose monophosphates were increased, whereas that of fructose 1,6-diphosphate was decreased; similar changes in the concentrations of hexose phosphates were observed when hearts from normal rats were perfused with medium containing fatty acids or ketone bodies. These changes have been attributed specifically to inhibition of the phosphofructokinase reaction by these factors. In hypophysectomized or adrenalectomized rats the induction of alloxan-diabetes or starvation did not (as in the normal rat) change the concentrations of hexose phosphates. In alloxan-diabetic hypophysectomized rats treatment with growth hormone and cortisol led to changes in hexose phosphates similar to those seen in diabetic rats. The effects of alloxan-diabetes and starvation, and of fatty acids and ketone bodies, on the concentrations of hexose phosphates were not observed in hearts perfused anaerobically of (under aerobic conditions) with medium containing salicylate or 2,4-dinitrophenol. Evidence is presented for similar effects of alloxan-diabetes and starvation on the concentrations of hexose phosphates in rat heart in vivo. The concentration of ATP in rat heart was decreased by anaerobic perfusion, whereas those of AMP and inorganic phosphate were increased. Alloxan-diabetes and starvation, and fatty acids and ketone bodies, had no consistent effects on the concentrations of ATP, AMP and inorganic phosphate. It is suggested that anoxia may activate phosphofructokinase by lowering the intracellular concentration of ATP (an inhibitor of the enzyme) and increasing that of AMP and inorganic phosphate (activators of the enzyme). It is suggested that alloxan-diabetes and starvation, and fatty acids and ketone bodies, decrease the rate of the phosphofructokinase reaction by raising the intracellular concentration of citrate (an inhibitor of the enzyme). The possibility that the inhibitory effects of alloxan-diabetes and starvation on the phosphofructokinase reaction are due to an increased rate of respiration of fatty acids derived from muscle glycerides is discussed.