EFFECTS OF EXOGENOUS AND ENDOGENOUS INSULIN ON GLUCOSE UTILIZATION AND PRODUCTION *

Recent findings reported in the literature concerning the mechanism of insulin action are in some respects contradictory. The observations originally made by Gemmil11-3 that the addition of insulin to the incubation medium enhances the glucose uptake and glycogen formation by the isolated diaphragm were amply confirmed by subsequent investigator^.^ From these and other observations it has been postulated that endogenous insulin likewise increases glucose utilization by peripheral tissues. More recently, Renold et U Z . , ~ studying the alterations of carbohydrate metabolism in diaphragm and in liver slices after the administration of insulin to diabetic rats for varying periods of time, found that insulin acted within minutes to increase glucose utilization (glucose uptake and glycogen formation), only in the peripheral tissues; the effects on the liver appeared only when the liver was extirpated many hours following injections of insulin into the diabetic animal. This led to the conclusion that the “immediate metabolic effects of insulin [are] a t the periphery only.” On the other hand, it has been suggested in several recent studies that the major, if not the exclusive, action of insulin is to inhibit hepatic glucose release. This suggestion is based on the changes in plasma glucose production and utilization observed following a subcutaneous injection of insulin into humans who received a single trace dose of CI4 glucoses and on arterial-hepatic-venous differences in blood glucose concentration during the course of insulin infusion (L. L. Madison, B. Combes, W. Strickland, R. Unger, and R. Adams, Unpublished data). It was postulated further that endogenous insulin secreted under physiological conditions exerts a similar effect on hepatic glucose release.s The studies reported here represent a continuation of earlier work7 undertaken to determine whether insulin exerts its action on the peripheral tissues to bring about increased removal and utilization of plasma glucose or on the liver to diminish the glucose production and release to the plasma, or both. The experiments were carried out on dogs without the use of general anesthesia and without any operative procedure, under truly physiological conditions, using C14 glucose.