Alcohol Hypoglycemia: II. A Postulated Mechanism of Action Based on Experiments with Rat Liver Slices1

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Abstract
Liver slices from fed and fasted rats were incubated in Krebs-Ringer phosphate (KRP) and Krebs-Ringer bicarbonate (KRB) with “tracer” and “substrate” quantities of uniformly abeled alanine-14C. The alanine was employed to provide a modulated generation of labeled pyruvate that might simulate the delivery of gluconeogenic precursor during starvation in vivo. The experimental manipulationswere designed to assess how the metabolic response to constant amounts of ethanol (10.0 mM) could be influenced by prevailing levels of pyruvate turnover (i.e., KRP vs. KRB); intrinsic intrahepatic pathways and preformed substrates (i.e., fed vs. fasted rats); and the availability of exogenous 3-carbon fragments (i.e., “tracer” vs. “substrate” alanine). Under conditions of limited pyruvate turnover and availability, ethanol inhibited the formation of glucose-14C and increased lactic acid-14C, although the consumption of oxygen was reduced only minimally. With “substrate” quantities of alanine in KRB, the net formation of glucose-14C was increased by ethanol in slices from fed animals, and increased, unaffected or depressed in slices from fasted rats. The concomitant changes in lactic acid-14C were smaller and reciprocally related. In the presence of ethanol, aspartic acid-14C invariably accumulated, and a consistent reduction in the oxidation of alanine to 14CO2 occurred. The inhibition of decarboxylation correlated most strikingly with the effects upon glucose-14C. Thus, in KRB, glucose-14C from “substrate” alanine was depressed whenever 14CO2 was reduced more than 50% whereas net gluconeogenesis was unaffected or increased when ethanol caused less than 50% inhibition of 14CO2. The relationships were not reduplicated by substituting equimolar amounts of acetate for the ethanol, and hence they cannot be ascribed to dilution of isotope by unlabeled 2-carbon fragments. On the basis of the present findings, it has been postulated that the bidirectional effects upon glucose14C are conditioned by the alterations in the ratio of NAD H2/NAD which arise in the liver during alcohol oxidation and by the pathways that are employed for the disposition of the extra “reducing equivalents” Cytoplasmic reoxidation of NADH2 via the reductive step in the biosynthesis of glucose could abet gluconeogenesis, whereas self-perpetuating inhibition of gluconeogenesis could occur when increased proportions of the NADH2 are oxidized within the mitochondria because extramitochondrial hydrogen acceptors are limited. The “gluconeogenic set” that prevails in the liver at the time of alcohol oxidation has been assigned a pivotal role in these alternative possibilities, and it has been suggested that the intrahepatica vailability and turnover of pyruvate may be major determinants of the “set” Experiments with L-sorbitol, as another NADH2-generating system, have been presented to support the provisional hypothesis.