SINCE the action of insulin began to be investigated, a puzzling discrepancy between its action on the diabetic and on the normal animal has attracted attention. In the diabetic animal it readily renews the store of glycogen in the depleted liver; on the other hand, the predominant result of the earlier and of much of the later work was to show that, when injected into the normal animal, if it measurably affected the glycogen in the liver or the muscles, it caused disappearance instead of additional accumulation [cf. Dudley and Marrian, 1923; Macleod and McCormick, 1923;Babkin, 1923; Nitzescu and Popescu-Inotesti, 1923; Brugsch, 1924; Gigon and Staub, 1923]. There was evidence, indeed, that insulin even in the normal animal might initially promote an increase of glycogen in the liver of the rabbit [Cori, Cori and Pucher, 1923], or of the whole mouse [Bissinger, Lesser and Zipf, 1923], though at a later stage of developed hypoglycaemia the glycogen became reduced below the original amount. Cori later found that insulin caused diminution of liver-glycogen in rabbits, guinea-pigs and mice when the proportion was initially high, but not if it was low. There was no room for doubt, however, that the glycogen stores of liver and muscles might in some species be seriously depleted by insulin with a concurrent great reduction of oxidative metabolism; and the problem remained of accounting for the disappearance of circulating glucose under such conditions.Macleod [1926] and his school have interpreted such results as pointing to the conversion of glucose into some substance unrecognisable by the ordinary methods of estimating carbohydrates, when insulin acts on the normal animal. It was found in this laboratory, however, that when insulin acted under uncomplicated conditions on muscle, the glucose disappearing could be fully accounted for by glycogen storage and oxidation [Best, Dale, Hoet and Marks, 1926]. It was accordingly urged that the phenomena seen in the whole animal were due to complication by another action of insulin, namely, a depression of the new formation of carbohydrate, so that oxidative metabolism was concentrated on that pre-existing, with consequent depletion of reserves.