Inhibition of glucose production and stimulation of bile flow by R (+)-α-lipoic acid enantiomer in rat liver

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 mumol 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 mumol min(-1) g(-1) ). RLA (10(-4) mol L-1 and 10(-3) mol L-1 ) stimulated bile flow by similar to 20 and similar to 50%, respectively (P < 0.02 vs. control). After 10(-3) mol L-1 RLA infusion, liver glycogen was similar to 3 fold higher (5.2 +/- 1.1 vs. control: 1.8 +/- 0.2 mumol g(-1) , P < 0.002). Also at low lactate concentrations (1 mmol L-1 ), 10(-3) mol L-1 RLA reduced glucose production by similar to 53% and lactate uptake by similar to 60%, but stimulated bile secretion by similar to 50% (P < 0.05). Conclusion: RLA reduces hepatic glucose release by inhibiting lactate- dependent glucose production in a concentration-dependent fashion.