Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process

Détaille, Dominique; Guigas, Bruno; Chauvin, Christiane; Batandier, Cécile; Fontaine, Éric; Wiernsperger, Nicolas; Leverve, Xavier

doi:10.2337/diabetes.54.7.2179

Cited by 230 publications

(199 citation statements)

References 40 publications

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…An et al (2006) showed that metformin reduces highfat-induced cardiac cell death, through inhibition of ceramide synthesis. Similarly, metformin was shown to prevent high glucose-induced endothelial cell death (Detaille et al, 2005). This discrepancy suggests that even though they both activate the AMPK pathway, AICAR and metformin mediate their effects through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

View full text Add to dashboard Cite

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

show abstract

Section: Discussionmentioning

confidence: 99%

“…AICAR is known to induce apoptosis while metformin was shown to protect endothelial cells from apoptosis (Detaille et al, 2005;Kim et al, 2007). LNCaP cells were incubated with metformin, AICAR and staurosporine as a control.…”

Section: Metformin Does Not Induce Apoptosismentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The LDH data suggest that the increase in expression of Hsp60 observed at both mRNA and protein levels were not due to cellular lysis and that the growth inhibitory effects of 500 μM metformin was not due to cell death but possibly due to metformin having an inhibitory effect on mitochondrial bionenergetic functions. Interestingly, metformin has been documented to prevent cell death by modulation of the mitochondrial permeability transition pore opening induced by a glutathione-oxidising agent t-butyl hydroperoxide (Guigas et al 2004) and also due to high glucose-induced cell death in a human dermal microvascular endothelial cell line, HMEC-1 (Detaille et al 2005). However, reports of metformin treatment resulting in an increase in H 2 O 2 production in rat liver mitochondria (Carvalho et al 2008), a short-term trial involving 15 type 2 diabetes mellitus patients treated with metformin showing an elevation in oxidative stress, indicated by elevated malidialdehyde levels (Škrha et al 2007) and metformin causing mitochondrial depolarization and oxidative stressdependent apoptosis in cultured glioma cells (Isakovic et al 2007), suggest that the role of mitochondria in metformininduced cytotoxicity remains to be of defined.…”

Section: Resultsmentioning

confidence: 99%

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Tsuei

Martinus

2012

Cell Stress and Chaperones

View full text Add to dashboard Cite

Metformin is in widespread clinical use for the treatment of diabetes mellitus in patients. It has been shown to inhibit mitochondrial bioenergetic functions by inhibiting complex I of the electron transport chain. The expression of mitochondrial-specific molecular stress protein Hsp60 is a key consequence of mitochondrial impairment. Since this protein has important immune-modulatory properties, we have investigated the expression of Hsp60 in human THP-1 monocyte cells exposed to metformin. In this study, we demonstrate significant up-regulation of Hsp60 at both mRNA and protein levels when these cells were exposed to metformin at therapeutic dosage levels. Interestingly, there was also an increase in expression of CD14 mRNA in these cells. This suggested a possible modulation of the differentiation rates of the THP-1 cells during exposure to metformin. As monocyte differentiation marks a critical step in atherosclerosis, these observations suggest that longterm exposure to metformin could have important implications for the diabetic patient.

show abstract

“…Moreover, it has also been shown that metformin inhibits mitochondrial complex I activity leading to the impairment of mitochondrial function [5][6][7]. However, it has also been shown that metformin prevents the mitochondrial permeability transition pore (PTP) opening in both permeabilized and intact KB cells [8], and in permeabilized human microvascular endothelial cells (HMEC-1) [9]. In opposition, Isakovic et al [10] reported that metformin acts as a PTP inducer in C6 rat glioma cell line.…”

Section: Introductionmentioning

confidence: 92%

Metformin promotes isolated rat liver mitochondria impairment

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process

Cited by 230 publications

References 40 publications

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Metformin promotes isolated rat liver mitochondria impairment

Contact Info

Product

Resources

About