Abstract
The influence of Ca2+ on hepatic gluconeogenesis was measured in the isolated perfused rat liver at different cytosolic NAD(+)-NADH potentials. Lactate and pyruvate were the gluconeogenic substrates and the cytosolic NAD(+)-NADH potentials were changed by varying the lactate to pyruvate ratios from 0.01 to 100. The following results were obtained: a) gluconeogenesis from lactate plus pyruvate was not affected by Ca(2+)-free perfusion (no Ca2+ in the perfusion fluid combined with previous depletion of the intracellular pools); gluconeogenesis was also poorly dependent on the lactate to pyruvate ratios in the range of 0.1 to 100; only for a ratio equal to 0.01 was a significantly smaller gluconeogenic activity observed in comparison to the other ratios. b) In the presence of Ca2+, the increase in oxygen uptake caused by the infusion of lactate plus pyruvate at a ratio equal to 10 was the most pronounced one; in Ca(2+)-free perfusion the increase in oxygen uptake caused by lactate plus pyruvate infusion tended to be higher for all lactate to pyruvate ratios; the most pronounced difference was observed for lactate/pyruvate ratio equal to 1. c) In the presence of Ca2+ the effects of glucagon on gluconeogenesis showed a positive correlation with the lactate to pyruvate ratios; for a ratio equal to 0.01 no stimulation occurred, but in the 0.1 to 100 range stimulation increased progressively, producing a clear parabolic dependence between the effects of glucagon and the lactate to pyruvate ratio. d) In the absence of Ca2+ the relationship between the changes caused by glucagon in gluconeogenesis and the lactate to pyruvate ratio was substantially changed; the dependence curve was no longer parabolic but sigmoidal in shape with a plateau beginning at a lactate/pyruvate ratio equal to 1; there was inhibition at the lactate to pyruvate ratios of 0.01 and 0.1 and a constant stimulation starting with a ratio equal to 1; for the lactate to pyruvate ratios of 10 and 100, stimulation caused by glucagon was much smaller than that found when Ca2+ was present. e) The effects of glucagon on oxygen uptake in the presence of Ca2+ showed a parabolic relationship with the lactate to pyruvate ratios which was closely similar to that found in the case of gluconeogenesis; the only difference was that inhibition rather than stimulation of oxygen uptake was observed for a lactate to pyruvate ratio equal to 0.01; progressive stimulation was observed in the 0.1 to 100 range. f) In the absence of Ca2+ the effects of glucagon on oxygen uptake were different; the dependence curve was sigmoidal at the onset, with a well-defined maximum at a lactate to pyruvate ratio equal to 1; this maximum was followed by a steady decline at higher ratios; at the ratios of 0.01 and 0.1 inhibition took place; oxygen uptake stimulation caused by glucagon was generally lower in the absence of Ca2+ except when the lactate to pyruvate ratio was equal to 1. The results of the present study demonstrate that stimulation of gluconeogenesis by glucagon depends on Ca2+. However, Ca2+ is only effective in helping gluconeogenesis stimulation by glucagon at highly negative redox potentials of the cytosolic NAD(+)-NADH system. The triple interdependence of glucagon-Ca(2+)-NAD(+)-NADH redox potential reveals highly complex interrelations that can only be partially understood at the present stage of knowledge.
Highlights
Primarily mediated by cAMP, the action of glucagon on hepatic metabolism can be influenced by several factors
The results of the present study demonstrate that stimulation of gluconeogenesis by glucagon depends on Ca2+
In the specific case of gluconeogenesis there are two factors that seem to be of striking importance: a) the intracellular concentration and distribution of Ca2+ [1] and b) the redox state of the NAD+-NADH couple [2]
Summary
Primarily mediated by cAMP, the action of glucagon on hepatic metabolism can be influenced by several factors. As a consequence of these Ca2+ movements, i.e., influx and release from the intracellular pools, administration of glucagon to the liver cells is followed by an increase in the cytosolic Ca2+ concentration [9,10]. Gluconeogenesis is an energy-dependent process and several respiratory enzymes are sensitive to Ca2+ [13]. It was demonstrated in the perfused liver that the effects of suboptimal glucagon concentrations on oxygen consumption were more pronounced when Ca2+ was present as opposed to the condition in which Ca2+ was omitted from the perfusion fluid and the intracellular pools had been exhausted [14]
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