Interaction of thyroid hormones and cyclic AMP in the stimulation of hepatic gluconeogenesis

Abstract

The possible interaction of l-3,3′,-5-triiodthyronine (T 3) and cycli AMP on hepatic gluconeogenesis was investigated in perfused livers isolated from hypothyroid rats starved for 24 h. T 3 (1·10 −6) and cyclic AMP (2·10 −4 M) increased hepatic gluconeogenesis from alanine within 30–60 min perfusion time (+85%/ + 90%), both were additive in their action (+191%). Concomitantly, α-amino[ 14C]isobutyric acid as well as net alanine uptake and urea production were elevated by T 3 and by cyclic AMP. T 3 increased the oligomycin-sensitive O 2 consumption and the tissue ‘overall’ ATP/ADP ratio, whereas cyclic AMP showed only a minor effect on cellular energy metabolism. As was observed recently for cyclic AMP, the stimulating action of T 3 on hepatic gluconeogenesis was independent of exogenous Ca 2+ concentration. T 3 by itself affected neither the total nor the protein-bound hepatic cyclic AMP contents, pyruvate kinese ( v:0.15 mM) activation nor the tissue levels of gluconeogenic intermediates. In contrast, cyclic AMP itself — although less effective than in euthyroid livers — decreased pyruvate kinase activity in hypothyroid livers with a concomitant increase in hepatic phospho enolpyruvate concentration. This resulted in a ‘crossover’ between pyruvate and phospho enolpyruvate. Cyclic AMP action was not affected by the further addition of T 3. Glucagon (1·10 −8 M) was less effective in hypo-than in euthyroid livers in increasing endogenous cyclic AMP content, deactivating pyruvate kinase and stimualting glucose production; this is normalized by the further addition of 1-methyl-3-isobutylxanthine (50 μM). It is concluded that T 3 stimulats hepatic gluconeogenesis by a cyclic-AMP-independent mechanism. In addition, the stimulatory action of cyclic AMP and glucagon with respect to hepatic gluconeogenesis is reduced in hypothyroidism. This may be explained by an increase in hepatic phosphodiesterase activity.