BIGUANIDES MAY PRODUCE HYPOGLYCEMIC ACTION IN ISOLATED RAT HEPATOCYTES THROUGH THEIR EFFECTS ON L-ALANINE TRANSPORT

We investigated the mechanisms of the effects of the biguanides metfor min and buformin on hepatic gluconeogenesis in hepatocytes isolated fr om normal rats. Both 10 nM glucagon and 50 muM dibutyryl cAMP increase d [H-3]alanine uptake in isolated hepatocytes of normal rats by about 150% and 55%, respectively, compared with the effect of 5 mM alanine a lone. Metformin (3 mM) reduced glucagon-stimulated [H-3]alanine uptake to the level seen with alanine alone; buformin (3 mM) inhibited gluca gon-stimulated [H-3]alanine uptake by about 69%. The effects of biguan ides on dibutyryl cAMP-stimulated [H-3]alanine uptake were similar, bu t of smaller magnitude compared with those observed in the presence of glucagon. Ouabain (3 mM) had a stonger inhibitory effect on [H-3]alan ine uptake than the biguanides. However, 3 mM tolbutamide failed to su ppress [H-3]alanine uptake in the presence or absence of glucagon or d ibutyryl cAMP. Our results suggest that the inhibition of alanine upta ke, related to a reduction in the Na+/L-alanine transport system, is a possible mechanism of biguanide-related inhibition of hepatic glucone ogenesis.