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

Abstract

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 intramitochondrial oxidation of DPNH which results from alcohol metabolism inhibits oxidation of fatty acids, acetyl CoA generation and subsequently gluconeogenesis. DIABETES 16: 784-90, November, 1967. Alcohol is currently believed to inhibit gluconeogenesis as a result of its effect on cellular redox state. 1 In the absence t?f adequate supplies of cytoplasmic hydrogen acceptors necessary for substrate reoxidation of the DPNH resulting from alcohol metabolism, 2 gluconeogenesis is inhibited. This mechanism, however, has been derived primarily from studies with rat liver slices under experimental conditions which have no in vivo counterpart. Inhibition of gluconeogenesis has been demonstrated consistently only when liver slices have been obtained from fed and fasted animals and incubated in Krebs-Ringer phosphate buffer, a medium in which basal gluconeogenesis is already limited, or when tissue was obtained from fasted animals and incubated in Krebs-Ringer bicarbonate buffer in the absence of substrate. 2 Because recent studies have demonstrated that From the Medical College of Alabama, Birmingham, Alabama. maintenance of glucose production by rat liver is dependent upon an adequate extrahepatic supply of substrate, 3 the question is raised whether or not there are other mechanisms by which alcohol inhibits gluconeogenesis in the rat and perhaps other animals. Since the use of the liver slice as a means for studying gluconeogenesis has been questioned, 4 the effects of alcohol on glucose production were investigated with use of an in vitro preparation which allows closer simulation of conditions known to exist in vivo.In the studies to be described, the effects of increasing concentrations of alcohol on glucose production and cellular redox state were investigated in an attempt to dissociate the abilities of alcohol to alter redox state and inhibit gluconeogenesis. The rationale for this approach was that alterations in gluconeogenesis would be independent of the cellular redox state once sufficient alcohol was present to saturate the metabolic pathways for alcohol degradation and assure its constant metabolism. METHODSLiv...

Ethanol-induced hyperlacticacidemia: inhibition of lactate utilization

“…DISCUSSION It has been suggested that ethanol-induced hyperlacticacidemia is due to the increased availability of NADH in liver which results from the metabolism of ethanol and a subsequent increase in pyruvate conversion to lactate (1-3). However, studies of the effect of ethanol on lactate production by the perfused rat liver (16)(17)(18) or on hepatic vein lactate in man (15) do not support the contention that the liver is the source of the lactate.…”

“…In fact, in these experiments, ethanol decreased lactate and pyruvate production by the isolated perfused rat liver (17,18), as well as their concentration in liver tissue (18); and the increased lactate to pyruvate ratio was a result of greater decrease in pyruvate than in lactate. In similar studies in which rat livers were perfused with diluted whole blood, ethanol only increased hepatic lactate production by livers from starved rats (16), yet it is well known that ethanol induces hyperlacticacidemia in the fed and fasted state.…”

“…In isolated rat livers perfused with an artificial buffer containing alanine as substrate, the ratio of lactate to pyruvate in the perfusate is invariably increased by ethanol, but lactate production is not (17,18). In fact, in these experiments, ethanol decreased lactate and pyruvate production by the isolated perfused rat liver (17,18), as well as their concentration in liver tissue (18); and the increased lactate to pyruvate ratio was a result of greater decrease in pyruvate than in lactate.…”

“…In fact, the one study in which appropriate data are available indicates that ethanol decreases hepatic lactate removal rather than increasing production (15). Furthermore, studies with the isolated perfused rat liver (16)(17)(18) do not indicate that ethanol increases hepatic lactate production.…”

Interference of Ethanol and Sorbitol with Hepatic Ketone Body Metabolism in Normal, Hyper‐ and Hypothyroid Rats

“…Clinical findings are mainly based on diabetic patients, in whom alcohol has usually been found to have a slightly depressing effect, if any, on ketonaemia [15,16,33,34]. Perfusion experiments on livers of starved rats [6] and investigations in vivo using starved or fed rats [7,8] indicate a tendency towards increase after acute administration, although an opposite effect has also been reported [35]. The mode of administration, the amount given and the time elapsed before determining the effect seem to be relevant factors in the interpretation of the interference of ethanol with ketogenesis.…”