Metformin (1,1-dimethylbiguanide: MET) is used in the treatment of type 2 d
iabetes mellitus. MET's antihyperglycemic action depends at least in part o
n its inhibitory effect on hepatic gluconeogenesis. As to gluconeogenesis f
rom amino acids (e.g. L-alanine), this is associated with an inhibition Of
L-alanine uptake into hepatocytes. Since this uptake is mediated by an elec
trogenic transport mechanism. the aim of the present study was to investiga
te whether MET has an influence on the liver cell membrane potential which
might explain its inhibitory effect on L-alanine uptake. The experiments we
re performed in vivo in anesthetized rats and in vitro using superfused mou
se liver slices with the conventional microelectrode technique. In vivo. ME
T (160 mg/kg intraperitoneally (i.p.)) significantly depolarized (dV) the l
iver cell membrane by 6 mV. MET (1 mmol/l) also depolarized the liver cell
membrane in vitro (e.g. 15 min after start of superfusion: dV = 8 mV). MET'
s effect was at least partly reversible. Glucagon (10(-7) Mol/l), which hyp
erpolarized the liver cell membrane, abolished MET's effect. Further. the M
ET-induced depolarization was completely absent during superfusion with low
Cl- ([Cl-] = 27 mmol/l) medium. and significantly attenuated by the Cl- ch
annel blocker NPPB (25 mu mol/l). While MET's effect was only somewhat atte
nuated by blockade of the Na+/K+/2Cl(-) cotransporter or by superfusion wit
h (HCO3--free) HEPES buffer, the carboanhydrase blocker acetazolamide (1 mm
ol/l) or blockade of the HCO3-/Cl- exchanger by DIDS (100 mu mol/l), which,
however, also blocks Cl- channels, abolished its effect. The depolarizatio
n of the liver cell membrane by MET was unaffected by a blockade of K+ chan
nels with Ba2+. a blockade of the Na+/K+ pump or superfusion with low Na+ m
edium ([Na+] = 26 mmol/l), According to these results. the MET-induced depo
larization of the liver cell membrane could be due to an activation of the
Cl-/HCO3- exchanger and thus depend on intracellular HCO3- formation. This
activation could then lead to a disturbance of the equilibrium between intr
a- and extracellular Cl- and therefore to an enhanced Cl- efflux via Cl- ch
annels. It is plausible that the depolarizing effect induced by MET is asso
ciated with its inhibitory effect on gluconeogenesis by inhibiting uptake o
f L-alanine and other amino acids into hepatocytes. (C) 2001 Elsevier Scien
ce BN. All rights reserved.