The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients

Ersoy, Canan; Kıyıcı, Sinem; Budak, Ferah; Oral, Barbaros; Güçlü, Metin; Duran, Cevdet; Selimoğlu, Hadi; Ertürk, Erdinç; Tuncel, Ercan; İmamoğlu, Şazi

doi:10.1016/j.diabres.2008.02.006

Cited by 118 publications

(73 citation statements)

References 35 publications

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“…However, the mechanism underlying the anticancer effects of metformin remain to be fully elucidated Previous studies have shown that, despite the complexity of the molecular signaling mechanisms of metformin, several critical molecules and pathways have been confirmed to be involved in this regulation, including the activation of AMPK (8,18), inhibition of mammalian target of rapamycin complex-1 (19), interruption of the crosstalk between insulin and insulin-like growth factor-1 receptor (20) and reductions in the expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 (21).…”

Section: Discussionmentioning

confidence: 99%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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Abstract. The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC-27 and MKN-45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma-associated oncogene (Gli)-1, Gli-2 and Gli-3 were examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP-activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli-1 were decreased by metformin treatment in the two cell lines in a dose-and time-dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli-2 and Gli-3. The small interfering RNA-induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh-induced expression of Gli-1 in HGC-27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent. IntroductionGastric cancer is one of the most common types of malignant cancer worldwide (1). In addition tosurgery, chemotherapy and radio chemotherapy, there is a demand for novel treatment approaches for gastric cancer due to its poor prognosis (2).Metformin is a widely used anti-diabetic drug, which has been reported to exhibit potential anticancer activity (3). Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4-6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7). However, the mechanism underlying the anticancer effects of metformin is complex and remains to be fully elucidated. Activation of the AMP-activated protein kinase (AMPK) pathway has been recognized as a key aspect of the anticancer effects of metformin (8).The Sonic hedgehog (Shh) signaling pathway is one of the most common signal transduction pathways in human cells (9). It is critical in normal cell differentiation and embryonic development (10). However, abnormal activation of the Shh pathway has been identified in several types of human cancer (11). Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of m...

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Section: Discussionmentioning

confidence: 99%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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“…The Mann-Whitney test was utilised in a post hoc analysis to compare the individual groups. Letters indicate statistical significance between groups (P < 0AE05 [21], suggesting that chronic hyperglycaemia may increase VEGF secretion and that reduction in elevated levels of VEGF may be possible with improved glycaemic control [28]. However, Loebig et al [4] showed a lack of association of VEGF with insulin sensitivity in normal-weight and obese subjects, and VEGF levels remained unchanged in patients with type 1 diabetes after 210 min of hyperglycaemia (12AE0 mM) and normoglycaemic (5AE0 mM) clamps with high (120 mU ⁄ kg ⁄ h) and standard insulin infusions (30 mU ⁄ kg ⁄ h), respectively [29].…”

Section: Controlsmentioning

confidence: 99%

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹

Siervo

Tomatis

Stephan

et al. 2012

Eur J Clin Investigation

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Eur J Clin Invest 2012; 42 (9): 967–973 Abstract Background Increased levels of vascular endothelial growth factor (VEGF) have been observed in patients with metabolic syndrome (MetS). Nitric oxide (NO) formation is reduced in MetS, but its relationship to VEGF production remains poorly defined. We evaluated the association between VEGF/NO synthesis and insulin sensitivity in obese subjects and investigated the secretory response of VEGF to an acute elevation of glucose. Materials and methods Seven healthy normal‐weight subjects, seven obese subjects without MetS and seven obese subjects with MetS were recruited. Anthropometry, body composition and cardiometabolic functions (blood pressure, glucose, insulin, triglycerides, total cholesterol, HDL‐C and VEGF) were measured, and a novel stable isotope method was used to assess in vivo rates of NO production. A frequent sampling intravenous glucose tolerance test was performed to study the dynamics of VEGF release. Results Fasting VEGF levels were significantly higher in the two obese groups compared to the control group (P for trend = 0·02), but the difference was not significant after adjustment for age. Vascular endothelial growth factor levels were associated with systolic blood pressure (ρ = 0·54; P = 0·01) and NO production (ρ = −0·44; P = 0·04). Vascular endothelial growth factor levels increased in response to acute hyperglycaemia in normal‐weight and obese subjects (P < 0·001). Conclusions Vascular endothelial growth factor levels rapidly increase during hyperglycaemia and are inversely related to NO production at steady state. The potential link between the acute secretion of VEGF and atherosclerotic risk in subjects with poorly controlled glycaemia as well as the potential of lowering elevated VEGF levels by increasing NO production and/or availability warrants further investigation.

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“…Por otro lado, y de forma no dependiente de insulina, la activación de la AMPK, como principal determinante en la vía anticancerígena, produce la inhibición de la señalización Phosphatidylinositol-4,5-bisphosphate 3-kinase, AKT y R Mammalian Target of Rapamycin, fundamental en la patogenia de la carcinogénesis [115][116][117] . Adicional a los efectos antineoplásicos, también han sido reportadas propiedades anti-metastásicas, al inhibir la angiogénesis, mecanismo pilar del fenómeno de metástasis, al reducir los niveles del factor de crecimiento endotelial vascular tipo 1, Inhibidor Plasmático del Factor activador Plasminógeno 1 (PAI-1) , Metalopreinasas de Matriz tipo 2 y tipo 9 [118][119][120][121] , así como el bloqueo del potencial invasivo celular, tras la inversión de la transición mesénquima-epitelio mediado por la inhibición del TGFβ 122,123 .…”

Section: El Estudio the Glycometabolic Intervention As Adjunct To Priunclassified

Metformina: más allá del control glucémico

Morantes-Caballero

Londoño-Zapata

Rubio-Rivera

et al. 2017

revmed

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RESUMENIntroducción: la metformina es una biguanida que disminuye gluconeogénesis e incrementa la recaptación de glucosa en los músculos, sin embargo, más allá del glucémico se han documentado beneficios adicionales como la disminución de complicaciones crónicas derivadas de la hiperglucemia, entre ellas las cardiovasculares y del síndrome metabólico per se. Objetivo: identificar los efectos de la metformina diferentes al control control glucémico en población con diabetes mellitus, con el fin de contribuir a difundir el conocimiento. Materiales y método: tres revisores independientes realizaron la búsqueda en distintas bases de datos entre ellas Pubmed y ScienceDirect, utilizando los términos Metfomin AND Cardiovascular disease AND inflamatory response AND Hyperlipidemia, Biguanides, Diabetes Mellitus, Diabetes complications, Obesity, Vascular diseases AND Cancer; y Metfomina y enfermedad cardiovascular, metformina y cáncer se seleccionaron los artículos desde el año 2010, encontrando 13 828 artículos, de los cuales se incluyeron 144. Conclusión: más allá del control glucémico, la metformina, modifica la "memoria metabólica", reduce mediadores inflamatorios y el grosor de pared arterial, disminuye factores trombóticos y reduce la prevalencia de falla cardiaca logrando impactar la morbimortalidad y mediante cambios moleculares o genéticos, tiene potencial uso como anticancerígeno. El clínico debe conocer estos efectos para favorecer su pronto inicio en los casos indicados. Metformin: beyond the glycemic targetABSTRACT Introduction: the metformin is a biguanide which main action is to decrease hepatic glucose output, primarily by decreasing gluconeogenesis, and increase glucose uptake by muscles. However, beyond the glycemic target, additional benefits have been documented like a decrease in chronic complications to hyperglycemia, including cardiovascular comorbility and metabolic syndrome. Objetive: to identify effects of metformin other than glycemic control in patients with diabetes mellitus in order to help disseminate knowledge. Materials and methods: three independent reviewers searched in different databases of PubMed and ScienceDirect using the DeCS and MeSH terms: Metfomin AND Cardiovascular disease AND inflamatory response AND Hyperlipidemia, Biguanides, Diabetes Mellitus, Diabetes complications,Obesity, Vascular diseases AND Cancer, selecting the items since 2010 year and prior to warrant mention. Search based publications that were considered most relevant and, additionally, a manual search of the referenced articles in publications retrieved in the initial search was conducted, 13 828 articles were found but 144 were included finally. Conclusion: beyond glycemic control, Metformin, modifies the "metabolic memory", reduces inflammatory mediators and thickness of arterial wall, decreases thrombotic factors and reduces the prevalence of heart failure making an impact morbidity and mortality and because of molecular or genetic changes, it has potential use as anticarcinogenic. The physicians should know...

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The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients

Cited by 118 publications

References 35 publications

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹

Metformina: más allá del control glucémico

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The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients

Cited by 118 publications

References 35 publications

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia1

Metformina: más allá del control glucémico

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VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹