Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain

被引:1735
作者
Owen, MR [1 ]
Doran, E [1 ]
Halestrap, AP [1 ]
机构
[1] Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England
关键词
gluconeogenesis; glucose utilization; lactic acidosis; mitochondria; NIDDM;
D O I
10.1042/0264-6021:3480607
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although metformin is widely used for the treatment of noninsulin-dependent diabetes, its mode of action remains unclear. Here we provide evidence that its primary site of action is through a direct inhibition of complex 1 of the respiratory chain. Metformin (50 mu M) inhibited mitochondrial oxidation of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60h exposure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whereas in submitochondrial particles inhibition was immediate but required very high metformin concentrations (K-0.5, 79 mM). These data are compatible with the slow membrane-potential-driven accumulation of the positively charged drug within the mitochondrial matrix leading to inhibition of complex 1. Metformin inhibition of gluconeogenesis from L-lactate in isolated rat hepatocytes was also time- and concentration-dependent, and accompanied by changes in metabolite levels similar to those induced by other inhibitors of gluconeogenesis acting on complex 1. Freeze-clamped livers from metformin-treated rats exhibited similar changes in metabolite concentrations. We conclude that the drug's pharmacological effects are mediated, at least in part, through a lime-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues. Lactic acidosis, an occasional side effect, can also be explained in this way.
引用
收藏
页码:607 / 614
页数:8
相关论文
共 38 条
[1]  
AKERBOOM TPM, 1979, TECHNIQUES METABOL B, V205, P1
[2]   METFORMIN DECREASES GLUCONEOGENESIS BY ENHANCING THE PYRUVATE-KINASE FLUX IN ISOLATED RAT HEPATOCYTES [J].
ARGAUD, D ;
ROTH, H ;
WIERNSPERGER, N ;
LEVERVE, XM .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1993, 213 (03) :1341-1348
[3]   Drug therapy - Metformin [J].
Bailey, CJ ;
Turner, RC .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (09) :574-579
[4]   ENERGETICS OF EHRLICH ASCITES MITOCHONDRIA - MEMBRANE-POTENTIAL OF ISOLATED-MITOCHONDRIA AND MITOCHONDRIA WITHIN DIGITONIN-PERMEABILIZED CELLS [J].
BOGUCKA, K ;
WRONISZEWSKA, A ;
BEDNAREK, M ;
DUSZYNSKI, J ;
WOJTCZAK, L .
BIOCHIMICA ET BIOPHYSICA ACTA, 1990, 1015 (03) :503-509
[5]  
CHAPPELL JB, 1963, J BIOL CHEM, V238, P410
[6]  
COOK DE, 1973, J BIOL CHEM, V248, P5272
[7]  
DAVIDOFF F, 1971, J BIOL CHEM, V246, P4017
[8]   HYPOXIA AND MITOCHONDRIAL INHIBITORS REGULATE EXPRESSION OF GLUCOSE TRANSPORTER-1 VIA DISTINCT CIS-ACTING SEQUENCES [J].
EBERT, BL ;
FIRTH, JD ;
RATCLIFFE, PJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (49) :29083-29089
[9]   Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I [J].
El-Mir, MY ;
Nogueira, V ;
Fontaine, E ;
Avéret, N ;
Rigoulet, M ;
Leverve, X .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (01) :223-228
[10]   THE MECHANISM OF ACTION OF PHENFORMIN IN STARVED RATS [J].
EVANS, PF ;
KING, LJ ;
PARKE, DV ;
MARGETTS, G ;
JONES, WE .
BIOCHEMICAL PHARMACOLOGY, 1983, 32 (22) :3459-3463