AIMS/BACKGROUND: R (+)-alpha-lipoic acid (RLA) has been suggested for the treatment of liver diseases, but has also been shown to improve glucose utilization in diabetic patients. Because detailed information of RLA action on carbohydrate metabolism in intact liver is lacking, we examined concentration-dependent effects of RLA on hepatic glucose production. METHODS: RLA (10(-6-)10(-3) mol L(-1)) or buffer (control) was infused in isolated livers of fasted rats during recirculating perfusion for 90 min (n = 4-6/group). Hepatic glucose and lactate fluxes and bile secretion were continuously monitored. RESULTS: RLA reduced lactate (10 mmol L(-1))-dependent glucose production in concentration-dependent fashion (R = - 0.780, P<0.001) by up to 67% compared with control (0.36 +/- 0.02 micromol min(-1) g(-1)). In parallel, RLA dose dependently decreased lactate uptake (R = - 0.592, P<0.001) also by up to 67% (control: 0.58 +/- 0.08 micromol min(-1) g(-1)). RLA (10(-4) mol L(-1) and 10(-3) mol L(-1)) stimulated bile flow by approximately 20 and approximately 50%, respectively (P<0.02 vs. control). After 10(-3) mol L(-1) RLA infusion, liver glycogen was approximately 3 fold higher (5.2 +/- 1.1 vs. control: 1.8 +/- 0.2 micromol g(-1), P<0.002). Also at low lactate concentrations (1 mmol L(-1)), 10(-3) mol L(-1) RLA reduced glucose production by approximately 53% and lactate uptake by approximately 60%, but stimulated bile secretion by approximately 50% (P<0.05). CONCLUSION: RLA reduces hepatic glucose release by inhibiting lactate-dependent glucose production in a concentration-dependent fashion.