Robert A. Kreisberg

Glucose-Lactate Inter-Relations in Man

THE roles of carbohydrate, lipid and protein metabolism in the fuel economy of fed, fasting and exercising man1 2 3 have provided an intriguing saga in modern scientific investigation of intermedia...

Effects of glucose-insulin-potassium on myocardial substrate availability and utilization in stable coronary artery disease: Studies on myocardial carbohydrate, lipid and oxygen arterial-coronary sinus differences in patients with coronary artery disease☆

To assess the metabolic effects of myocardial substrate alteration in patients with coronary artery disease, glucose-insulin-potassium solution was administered intravenously for 30 minutes to 14 men with stable angiographically documented coronary artery disease. The glucose-insulin-potassium solution (300 g of glucose, 50 units of regular insulin and 80 mEq of potassium chloride per liter of water) was infused at a constant rate in each patient, but individual infusion rates ranged from 0.013 to 0.032 ml/kg per min (4 to 10 mg glucose/kg per min) in the 14 patients. Simultaneous arterial and coronary sinus samples were obtained at 15 minute intervals during a stable 30 minute control period and again at 15 minute intervals during the infusion; samples were assayed for glucose, lactate, free fatty acid and oxygen content. In all 14 patients, during the glucose-insulin-potassium infusion, arterial glucose and lactate increased and arterial free fatty acid levels fell; the magnitude of the changes in arterial lactate and free fatty acids was related to the rate of infusion. Arterial-coronary sinus differences (A-Cs) for glucose, lactate and free fatty acid levels correlated with the arterial concentrations of these substrates (r = 0.66, 0.87 and 0.79, respectively). Regression analyses demonstrated myocardial thresholds for the uptake of these substrates as follows: glucose 79 mg/100 ml; lactate 300 mu mole/liter; and free fatty acids 100 to 200 mu Eq/liter. Finally and most importantly, the reduction in A-Cs oxygen values after glucose-insulin-potassium infusion correlated with the reduction in A-Cs free fatty acid levels (r = 0.64, P less than 0.0001). This observation suggests that, in patients with coronary artery disease, glucose-insulin-potassium infusion may significantly diminish myocardial oxygen requirements by reduction of myocardial free fatty acid utilization and simultaneous enhancement of myocardial carbohydrate utilization. Myocardial substrate availability may be an important determinant of myocardial oxygen demand in patients with coronary artery disease. Infusion of glucose-insulin-potassium solution has the potential to alter myocardial substrate availability, thus improving the balance between myocardial oxygen demand and supply.

Effect of Alcohol on Glucose Production and Lactate, Pyruvate and Ketone Body Metabolism by the Isolated Perfused Rat Liver

The purpose of these experiments was to determine whether the effect of ethanol on glucose production could be dissociated from its effect on the cytoplasmic DPN/DPNH ratio in the presence of adequate substrate. Isolated rat livers were perfused with a Krebs bicarbonate Ringer buffer containing 4 per cent albumin and 10 mM alanine in the presence of increasing concentrations of ethanol. Lactate, pyruvate, B-hydroxybutyrate and acetoacetate were used to reflect the cellular redox state. Despite producing maximum changes in lactate, pyruvate and ketone body metabolism, 10 mM ethanol did not inhibit glucose production. Ethanol concentrations of 20 and 40 mM produced no further change in the production of lactate and pyruvate but significantly inhibited ketone body and glucose production by the isolated perfused rat liver. These results are compatible with the proposal that increased entry and intramitochon-drial oxidation of DPNH which results from alcohol metabolism inhibits oxidation of fatty acids, acetyl CoA generation and subsequently gluconeogenesis.

Effect of Pancreatic Proteins on Insulin Assay Systems

The following proteins were analyzed for insulin-like behavior in the rat hemidiaphragm, rat fat pad, and two antibody immunoassay systems: ribonuclease A, deoxyribo-nuclease I, alpha-chymotrypsin, chymotrypsinogen A, tryp-sin, and trypsinogen. Chymotrypsin stimulated glucose uptake in the rat hemidiaphragm and behaved like insulin in the immunoassay system when the enzyme concentration was 7 × 10-6 M. No similar activity was found for any of the other proteins. Chymotrypsin was inactive at lower concentrations. The stimulation of glucose uptake in the rat hemidiaphragm by chymotrypsin was not prevented by the presence of guinea pig anti-insulin serum. This and other evidence suggests that the enhanced uptake of sugar is not due to insulin contamination and is probably a result of partial proteolysis of cell membrane with resulting increase in permeability. Mixtures of chymotrypsin with guinea pig anti-insulin serum and 1-131-labeled insulin under the conditions of the immunoassay were analyzed electrophoretically, and the results indicate partial hydrolysis of the labeled insulin. This hydrolysis probably accounts for the apparent insulin response produced by chymotrypsin in the two antibody immunoassay system.