Ca2+ dependence of gluconeogenesis stimulation by glucagon at different cytosolic NAD+-NADH redox potentials

Abstract

The influence of Ca 2+ 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 Ca 2+ 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 Ca 2+ , 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 a lactate/pyruvate ratio equal to 1. c) In the presence of Ca 2+ 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 Ca 2+ 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 Ca 2+ was present. e) The effects of glucagon on oxygen uptake in the presence of Ca 2+ showed a parabolic relationship with the lactate to pyruvate ratios which was closely similar to that found in the case of gluconeogenesis; Key wordsBraz J Med Biol Res 30 (7) 1997 A.C. Marques-da-Silva et al.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 Ca 2+ the effects of glucagon on oxygen uptake were different; the dependence curve was sigmoidal at the onset, with a welldefined 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 Ca 2+ except when the lactate to pyruvate ratio was equal to 1. The results of the prese...

Cafeteria Diet Feeding in Young Rats Leads to Hepatic Steatosis and Increased Gluconeogenesis under Fatty Acids and Glucagon Influence

“…This interpretation is corroborated by reports of glucose overproduction in obese animal models, associated with increased fructose-1,6-biphosphatase activity and protein levels [ 61 , 62 ]. Our results are also in line with previous findings [ 63 ] in which the glucagon stimulating action in gluconeogenesis is more pronounced at a high NADH/NAD + ratio. It should be mentioned that elevated plasma levels of this hormone have been found in obese, prediabetic, and type 2 diabetic conditions [ 20 , 64 , 65 ].…”

Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

“…The similar difference in the responses of oxygen uptake, on the other hand, can be explained in the same way if one assumes that the increment caused by octopamine on oxygen uptake in the fasted state is at least partly coupled to the oxidation of the reducing equivalents resulting from lactate oxidation. In fact, at least partial correlations between oxygen uptake increment and gluconeogenesis from lactate have been reported [26]. Experiments with the C. aurantium extract revealed inhibition of gluconeogenesis [16].…”

Responses of the perfused liver of neonatal type 2 diabetic rats to gluconeogenic and ammoniogenic substrates

“…Consequently a short-term up-regulation by glucagon must be considered as a real possibility. It must be mentioned, however, that the stimulatory effect of glucagon on gluconeogenesis is relatively modest unless the cytosolic NADH/NAD + ratio is very high [29,30]. Concerning the possible contribution of increased substrate concentrations one cannot expect a significant contribution from lactate.…”

“…There are several possibilities to be considered: 1) different concentrations of hormones able to stimulate gluconeogenesis; 2) higher substrate concentrations in the diabetic condition; 3) increased plasma concentrations of free fatty acid, which are known to estimulate gluconeogenesis [24][25][26][27][28]. With reference to the hormonal factors, it is known that glucagon, in addition to its medium-and long-term effects [16] can also promote short-term up-regulation of gluconeogenesis [29,30]. Insulin, in contrast, does not exert short-term effects in the liver [10,11].…”