Ms. Zaibi et al., METFORMIN INDUCES AN AGONIST-SPECIFIC INCREASE IN ALBUMIN PRODUCTION BY PRIMARY CULTURED RAT HEPATOCYTES, Biochemical pharmacology, 50(6), 1995, pp. 775-780
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.