Acute troglitazone action in isolated perfused rat liver

The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 μ M ) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin‐ and/or glucagon‐stimulated conditions in isolated perfused rat livers. During BSA‐free perfusion, high dose troglitazone increased basal ( P <0.01), but inhibited glucagon‐stimulated incremental glucose production by ∼75% (10.0±2.5 vs control: 40.0±7.2 μmol g liver −1 , P <0.01). In parallel, incremental lactate release rose ∼6 fold (13.1±5.9 vs control: 2.2±0.8 mmol g liver −1 , P <0.05), while bile secretion declined by ∼67% [0.23±0.02 vs control: 0.70±0.05 mg g liver −1 min −1 ), P <0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon‐stimulated glucose production, but rapidly increased lactate release ( P <0.0005) and portal venous pressure (+0.17±0.07 vs +0.54±0.07 cm buffer height, P <0.0001). These results indicate that troglitazone exerts both insulin‐like and non‐insulin‐like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.British Journal of Pharmacology (1999) 126 , 372–378; doi: 10.1038/sj.bjp.0702318