An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress

Bonnefont‐Rousselot, Dominique; Raji, Babatunde; Walrand, Stéphane; Gardès-Albert, Monique; Jore, D.; Legrand, Alain; Peynet, Jacqueline; Vasson, Marie‐Paule

doi:10.1053/meta.2003.50093

Cited by 150 publications

(93 citation statements)

References 29 publications

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“…3a and b), suggesting that the decrease in lipid peroxidation observed in the previous studies are not the result of a direct action of metformin but, probably, the result of its antihyperglycemic effects or the activation of AMPK [36]. Previously, Bonnefont-Rousselot et al [3] reported that metformin in vitro is able to scavenge hydroxyl (HO • ) but not O 2 -• , and that H 2 O 2 did not react with metformin. Our results show that metformin does not prevent H 2 O 2 production (Fig.…”

Section: Discussionmentioning

confidence: 80%

“…Zhou et al [2] reported that metformin activates AMP-activated protein kinase (AMPK), a major cellular regulator of lipid and glucose metabolism, in hepatocytes. Furthermore, it has been shown that metformin possesses a direct scavenging effect against oxygenated free radicals generated in vitro [3], and decreases intracellular production of reactive oxygen species (ROS) in aortic endothelial cells through the reduction of both NAD(P)H oxidase and/or the mitochondrial respiratory chain pathways [4]. Moreover, it has also been shown that metformin inhibits mitochondrial complex I activity leading to the impairment of mitochondrial function [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Metformin promotes isolated rat liver mitochondria impairment

et al. 2007

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Metformin, a drug widely used in the treatment of type 2 diabetes, has recently received attention due to the new and contrasting findings regarding its effects on mitochondrial function. In the present study, we evaluated the effect of metformin in isolated rat liver mitochondria status. We observed that metformin concentrations ‡8 mM induce an impairment of the respiratory chain characterized by a decrease in RCR and state 3 respiration. However, only metformin concentrations ‡10 mM affect the oxidative phosphorylation system by decreasing the mitochondrial transmembrane potential and increasing the repolarization lag phase. Moreover, our results show that metformin does not prevent H 2 O 2 production, neither protects against lipid peroxidation induced by the prooxidant pair ADP/Fe 2+ . In addition, we observed that metformin exacerbates Ca 2+ -induced permeability transition pore opening by decreasing the capacity of mitochondria to accumulate Ca 2+ and increasing the oxidation of thiol groups. Taken together, our results show that metformin can promote liver mitochondria injury predisposing to cell death.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Metformin promotes isolated rat liver mitochondria impairment

et al. 2007

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“…Unexpectedly, we found that metformin alone modified ovarian steroid synthesis (Figs 1 and 2). In fact, it has been reported that metformin alone modulates ovarian steroid synthesis in no-stimulated human leukocytes (Bonnefont-Rousselot et al 2003), no-stimulated granulosa cells (Tosca et al 2006b), and no-stimulated endometriotic stromal cells (Takemura et al 2007). However, the mechanisms involved remain unknown and studies are being designed to clarify this point.…”

Section: Discussionmentioning

confidence: 99%

Effect of DHEA and metformin on corpus luteum in mice

Sander¹,

Facorro²,

Piehl³

et al. 2009

Reproduction

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We evaluated the effect of hyperandrogenism in ovaries with functional and regressing corpora lutea (CL) and the action of metformin in preventing these possible alterations using a mouse model. To obtain a CL functional for 9G1 days, immature female mice of the BALB/c strain were injected i.p. with 10 IU/mouse of pregnant mare's serum gonadotropin (PMSG). DHEA (60 mg/kg body weight s.c., 24 and 48 h prior to kill) decreased both serum progesterone (P) and estradiol (E 2 ) levels and increased the activity of superoxide dismutase (SOD) from ovaries with functional CL (on day 5 after PMSG). It increased P and E 2 and the activities of SOD and catalase (CAT) and decreased lipoperoxidation of ovaries with regressing CL (on day 9 after PMSG). Treatment with DHEA did not affect the production of prostaglandin F 2a (PGF 2a ) or PGE by ovaries with functional CL, whereas DHEA decreased PGF 2a and increased PGE production by ovaries with regressing CL. Metformin (50 mg/kg body weight, orally) given together with DHEA restored E 2 levels from mice with ovaries with functional CL and serum P, PGF 2a and PGE levels, and oxidative balance in mice with ovaries with regressing CL. Metformin alone was able to modulate serum P and E 2 levels, lipoperoxidation, SOD and CAT, and the 5,5-dimethyl-1-pyrroline N-oxide/ % OH signal. These findings suggest that hyperandrogenism is able to induce or to rescue CL from luteolysis and metformin treatment is able to prevent these effects.

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“…One possible mechanism by which metformin improves atherosclerosis is its anti-thrombotic effects [26,27]. The other possible mechanism is its ability to modulate reactive oxygen species generation [28]. The reduction of systemic methylglyoxal concentration induced by metformin may also have a beneficial effect on IMT [29].…”

Section: Discussionmentioning

confidence: 99%

Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes

et al. 2004

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Aim/hypothesis. Metformin is a well-known oral hypoglycaemic agent and has been commonly used, in combination with sulphonylurea, to treat type 2 diabetes. However, the advantageous effect of metformin plus sulphonylurea on diabetic macroangiopathy has yet to be clarified. To evaluate whether sulphonylurea or sulphonylurea plus metformin prevent diabetic macroangiopathy, we examined the progression of carotid artery intima-media thickness (IMT) as a surrogate end point. Methods. Subjects with type 2 diabetes were divided into three groups, receiving the following treatments: (i) glibenclamide (n=59); (ii) gliclazide (n=30); and (iii) glibenclamide + metformin (n=29). Maximum IMT and average IMT (the greatest value among 6 average values of each 3 points including greatest thickness) were measured at the beginning and end of the observation period. Results. For the follow-up period of 3 years, the annual change in average IMT of the glibenclamide plus metformin group (0.003±0.048 mm) was smaller than that of the glibenclamide group (0.064±0.045 mm) and gliclazide group (0.032±0.036 mm) (p<0.0001 and p=0.043 respectively). In the gliclazide group, average IMT increased during the follow-up period, but annual change in average IMT was significantly smaller than that of the glibenclamide group (p=0.005). Glibenclamide + metformin or gliclazide also attenuated the progression of maximum IMT, compared with that of glibenclamide (0.041±0.105, 0.044±0.106, 0.114±0.131 mm/year respectively, p=0.029 and p=0.035 respectively). Multivariable regression analysis implied that administration of metformin or gliclazide significantly and independently (p<0.05) reduces the progression of average IMT, compared with glibenclamide monotherapy. Conclusions/interpretation. These data indicate that metformin or gliclazide, rather than glibenclamide, have a potent anti-atherogenic effect in type 2 diabetes.

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An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress

Cited by 150 publications

References 29 publications

Metformin promotes isolated rat liver mitochondria impairment

Metformin promotes isolated rat liver mitochondria impairment

Effect of DHEA and metformin on corpus luteum in mice

Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes

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