Hiram Woodward

Influence of Phenethylbiguanide on Lactic, Pyruvic and Citric Acids in Diabetic Patients

The biochemical effects of the oral hypoglycemic agent DBI (phenformin, phenethylbiguanide) in experimental animals have included alterations in the metabolism of lactic acid as well as of glucose, DBI not only increases the glucose uptake of the rat diaphragm in vitro but also decreases the oxygen uptake and increases the lactic acid production of that tissue. Lactic acid production by the guinea pig liver slice is also increased by the addition of DBI. In the same animal an elevation of the blood lactic acid concentration has been observed after administration of the drug. Accordingly, it appeared of interest to determine whether or not lactic acid metabolism was also altered in diabetic patients who were given DBI. The present studies on diabetic patients have included an investigation of the effects of DBI on ( i ) the concentration of lactic acid in the fasting blood, (2) the twenty-four-hour urinary excretion of lactic acid, (3) the changes in the blood lactic acid concentration after the administration of glucose or fructose, potential precursors of lactate, and (4) the changes in the blood lactic acid concentration after sodium lactate administration. Since lactate is in equilibrium with pyruvate, changes in lactic acid cannot be properly interpreted without a knowledge of the associated pyruvic acid changes. Therefore, both pyruvic and lactic acid concentrations were measured in the blood and urine specimens. In addition, changes in the blood concentrations and urinary excretions of glucose and citric acid were studied.

Studies of the effect of intravenous tolbutamide on pyruvic and lactic acid concentrations in peripheral venous blood in normal and diabetic subjects, and on splanchnic metabolism of fructose and glucose.

It has been known for some time that a blood sugar depression following the administration of insulin may be accompanied by concomitant elevations in blood pyruvate and blood lactate 1evels.l. 2 , Moorhouse and Kark4 have reported that the blood sugar depression following tolbutamide administration in a diabetic is not accompanied by these changes in pyruvate and lactate; and Hennes et aL6 have reported that in normal subjects the initial pyruvate change associated with hypoglycemia is an elevation following insulin, but a depression following tolbutamide. From this disparity the latter authors concluded that the hypoglycemic actions of the two agents are distinct and that a release of endogenous insulin is not the mechanism of action of tolbutamide. It was our objective to produce with insulin and tolbutamide (Orinase!) blood sugar depressions similar in magnitude and rate of fall and, under these conditions, to compare the pyruvate and lactate changes in both normal and diabetic subjects.

Metabolism of Fructose by the Liver of Diabetic and Non-Diabetic Subjects.∗

Summary and Conclusions The metabolism of fructose in the liver was investigated by hepatic vein catheterization studies in 3 diabetic patients deprived of insulin and in 3 non-diabetic subjects. (1) There was a large hepatic uptake of fructose during the period of intravenous administration in both diabetic and non-diabetic subjects. (2) In all but one case there was a large hepatic output of pyruvic and lactic acid during the fructose infusion. The liver of one diabetic patient in ketosis continued to remove pyruvic and lactic acid from the blood; hepatic glycogen depletion may have accounted for this divergent result. (3) In half the cases (2 diabetic patients and 1 non-diabetic subject) the output of glucose by the liver was increased during fructose administration. (4) In the absence of ketosis, the liver of the diabetic subject without insulin, therefore, metabolized fructose in a manner similar to that of the liver of the non-diabetic individual. The presence of ketosis, however, was accompanied by a decreased output of pyruvic and lactic acid, despite a normal uptake of fructose.