Depolarization of the liver cell membrane by metformin

Citation
Ta. Lutz et al., Depolarization of the liver cell membrane by metformin, BBA-BIOMEMB, 1513(2), 2001, pp. 176-184
Citations number
36
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
ISSN journal
00052736 → ACNP
Volume
1513
Issue
2
Year of publication
2001
Pages
176 - 184
Database
ISI
SICI code
0005-2736(20010806)1513:2<176:DOTLCM>2.0.ZU;2-9
Abstract
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.