The influence of hydrazine, phenelzine and nialamide on gluconeogenesis and cell respiration in the perfused guinea‐pig liver

Abstract

Hydrazine (2 mmol/l) and phenelzine (0.5 mmol/l), which are known to produce hypoglycaemia, inhibit glucose formation from lactate in the perfused guinea-pig liver. The hydrazone formed from pyruvate and phenelzine exerted the same effect at concentrations of only 0.05 mmol/l. It is suggested that the hydrazones are the substances which are effective. All these compounds inhibited pyruvate consumption and decreased CO2 production by the perfused liver which, togeteher with the pattern of hepatic metabolite concentrations, indicate that they diminish pyruvate metabolism. None of them influenced the activities in vitro of pyruvate carboxylase, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase. The hydrazone compound caused an increase of the ATP/ADP ration at lower concentrations and an opposite effect above 0.5 mmol/l. Nialamide, another hydrazine derivative, also reduced hepatic glucoeogenesis but led to a marked decrease in the hepatic ATP/ADP ratio and liver cell respiration accompanied by a rise in the 3-hydroxybutyrate/acetoacetate ratio.

Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice

“…Indeed, the hypoglycemic effect of phenelzine is well known in depressed, normal-weight, nondiabetic individuals [ 15 ]. This could be explained by several mechanisms of action, including an inhibition of jejunal glucose uptake [ 16 ], an inhibition of hepatic gluconeogenesis [ 17 ], and an enhancement of glucose-mediated insulin release from the pancreas [ 18 ]. It therefore becomes interesting to determine whether phenelzine treatment can reduce hyperglycemia in animal models of obesity or diabetes.…”

Synthesis and Hypoglycemic Activity of Benzamidophenyl-alkanoic Acid Derivates: New Inhibitors of Gluconeogenesis

“…Other inhibitors reported within the last 10 years include cyclopropanecarboxylic acid (12), phenelzine (13), tryptophan metabolites (14), 3-mercaptopicolinic acid (15), and aminopyrine (4), all effective in the range of 0.1-0.5 mM; 0.6 m M is reported for 2-bromooctanoate (16), 0.5-1.0 mM for pent-4-enoic acid (17), 2 mM for phenylpyruvate (18), and 5 mM for butylmalonate (19).…”

Oral Phenelzine Treatment Mitigates Metabolic Disturbances in Mice Fed a High-Fat Diet

“…The hypoglycemic effect of PHE reported in patients with depression and mood disorders (McIntyre et al, 2006) has been explained by hepatic gluconeogenesis inhibition, intestinal glucose uptake impairment, and/or enhanced insulin release (Aleyassine and Gardiner, 1975;Feldman and Chapman, 1975;Haeckel and Oellerich, 1977;Haeckel et al, 1984). According to an in vitro study with high PHE doses, the effect on insulin release is, however, the opposite (Aleyassine and Gardiner, 1975).…”

“…The hypoglycemic effect of PHE (McIntyre et al, 2006) may be caused by an inhibition of intestinal glucose uptake, hepatic gluconeogenesis, and alteration of pancreatic insulin release (Aleyassine and Gardiner, 1975;Feldman and Chapman, 1975;Haeckel and Oellerich, 1977;Haeckel et al, 1984). Given glycaemia restoration in HSD mice (Carpéné et al, 2018b), it becomes challenging to investigate whether PHE influences glucose homeostasis in insulin-resistant models.…”