METFORMIN INDUCES AN AGONIST-SPECIFIC INCREASE IN ALBUMIN PRODUCTION BY PRIMARY CULTURED RAT HEPATOCYTES

Metformin (MET) is known to increase several biological effects of ins ulin (INS), but there is no information concerning its direct effects on protein synthesis, We studied the action of MET on albumin producti on by primary cultures of freshly isolated rat hepatocytes, alone or i n combination with various agonists: INS, IGF-1, EGF, thyroxin, and de xamethasone. While having no effect alone, MET in vitro potentiates th e effects of INS, IGF-1, and EGF. When this increasing effect toward I NS was studied over a broad concentration range, MET appeared to impro ve low-acting INS levels and to intensify the mawimal INS effects. In contrast, MET did not change the production of albumin stimulated by t hyroxin or dexamethasone. Animals chronically pretreated with MET in v ivo showed a higher yield of isolated hepatocytes, better attachment, and especially higher viability after liver perfusion and during cell culture. This may largely explain why basal albumin rates were higher than in in vitro-treated cells, The effect of MET in the presence of t he agonists exhibited the same agonist-specificity as in vitro. Our da ta provide new insights into the pharmacology of MET by showing that h epatic protein synthesis is increased by MET and INS. From the specifi city of action of MET towards INS, IGF-1, and EGF (but not thyroxin or dexamethasone), we hypothesize that this biguanide may act on intrace llular pathways located between membrane receptors and sites of branch ing in the signaling cascades shared by these agonists.