The Action of Insulin on the Phosphate Cycle

The specific site of the chemical action of insulin has been the subject of much speculation. Insulin is apparently not essential for the synthesis or breakdown of carbohydrates. There is no positive evidence to indicate that insulin has any effect on the reactions of the Embden, Meyerhof, Parnas, and Cori schemes. Recent investigations have suggested that the action of insulin may be on the tricarboxylic acid cycle. Krebs and Eggleston (1) first demonstrated that insulin causes an increased oxidation of certain members of the tricarboxylic acid cycle in pigeon breast muscle. Although Shorr and Barker (2) failed to observe any influence of insulin in preparations of rabbit, cat, and dog muscle, the effect on pigeon breast muscle has been confirmed by others (3-5). Stare and Baumann (5) observed that while excised rabbit heart and skeletal muscle, and chicken breast muscle, are quantitatively less spectacular in their response to insulin, they respond qualitatively in the same manner as the more rapidly respiring pigeon breast muscle. In the course of the study of insulin action, Stare and Baumann (3) observed that injection of malonate in the intact animal prevented the hypoglycemic action of insulin. They also noted a temporary rise in blood sugar when malonate alone was administered. Rice and Evans (6) have reported that insulin induces an increased oxidation of pyruvate which could be inhibited by malonate. These authors found that insulin had no effect on the oxidation of citrate and of Lu-ketoglutarate. From these investigations it appears that insulin may have a catalytic effect on certain of the reactions of the Krebs’ tricarboxylic acid cycle. Since oxidation t,hrough the tricarboxylic acid system results in the formation of wph bond& (8,9), it is plausible to expect that malonate would influence the rise in liver ATP (adenosine triphosphate) which follows the administration of insulin. The experiments reported below were under-