Livers of fed normal and diabetic rats were perfused in the presence of glucose-l-C-14 and acetate-H-3 in order to study their metabolism with and without addition of insulin to the medium. Glucose was added to bring the initial medium level to 436 ± 6 mg./100 ml. Net glucose removal occurred only with normal rat livers. Livers of diabetic rats showed progressive impairment of glucose uptake and increase in glucose production as the interval from the last maintenance insulin injection was prolonged. Whereas these chronically diabetic animals had livers with low glycogen content, decreased lipogenesis, and increased uro genesis, rats which had received 1.5 U. protamine insulin on the previous day were fully hyperglycemic but yielded livers showing normal fatty acid and urea synthesis along with excessively high glycogen. Insulin addition lowered perfusate amino nitrogen levels with normal and diabetic livers but did not significantly affect glycemia in any series and had only small stimulatory effects on lipogenesis and glucose oxidation in livers of rats three to five days off insulin. The data suggest that although insulin has important direct effects on liver metabolism, its hepatic action does not explain its early in vivo hypoglycemic effect in diabetes.

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