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Following the independent observation of the additional hypoglycemic effect of the sulfonylureas in insufficiently insulin-treated pancreatectomized dogs1 it became evident that these compounds might produce the decrease in the blood sugar concentration of both normal and diabetic dogs by inhibiting, either partly or totally, the release of glucose from the liver.The first part of this report describes our experimental observations after applying the single injection of C14-labeled glucose for measuring the glucose output in the liver in normal dogs before and after intravenous injections of either tolbutamide or insulin.A new method for calculating this output from the isotope data was developed. By equaling the ratio between specific activity of glucose in samples of hepatic venous and arterial blood to the amount of glucose entering and leaving the liver, the output of unlabeled glucose from this organ could be calculated for any period before or after the administration of a substance producing a change in the size of the glucose pool. This method may have an advantage over the ordinary isotope-dilution method based upon injection of C14-glucose, which does not allow calculation of the glucose turnover during the actual changes of the plasma glucose concentration, as the latter will not necessarily be representative of the various compartments of the glucose pool.The second part of the report deals with the results obtained with this method when insulin was infused portally into normal, cyclopropane-anesthetized dogs. Eflect of Intravenous Injections of Tolbutamide or Insulin2These studies were performed in normal dogs, fasted overnight and anesthetized with pentobarbital sodium (Nembutal); a dose of about 200 pc. of uniformly labeled C14-glucose, representing about 2 mg. glucose, was injected intravenously. Following an equilibration for about 1 hour, blood samples were collected every 15 min. through a polyethylene catheter placed in a peripheral vein. After a control period of about 1 hour, a total dose of tolbutamide (0.15 gm./kg.) was injected intravenously in 2 doses (0.10 gm./kg. and 0.05 gm./kg., 10 min. apart) and blood samples were collected a t intervals of 10 to 30 min. for the next 2 to 5 hours. As shown in FIGURE 1, the exponential decrease of the blood glucose specific activity observed in the control period, which reflected a constant release of unlabeled glucose from the liver to replace the amount of glucose utilized in the peripheral tissues, was interrupted by the injection of the tolbutamide, as the specific activity remained almost constant for a period of 30 to 40 min. During this time the plasma glucose concentration decreased to about 40 to 50 mg. per cent. When these hypoglycemic levels were reached, the specific activity 557

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