Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

In the paper

“Gui et al.(75) published a systematic review and meta-analysis in which metformin was shown to be superior to insulin in reducing maternal weight gain during pregnancy as well as in the frequency of gestational hypertension (Figure 5a,); however, metformin did not change the frequency of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) fetuses or of hypoglycemia and preeclampsia(”

What the sources say

• Not checked yetcites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

In the paper

“We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (primary endpoint), but did decrease the frequency of preeclampsia (a secondary endpoint).”

In the paper

“Metformin has a molecular weight of 129 Dalton, and therefore, readily crosses the placenta.”

In the paper

“reduction of glucose absorbtion by the gastro-intestinal tract(44, 45)”

What the sources say

• Not checked yetcites [44] Natali, 2006, Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review, Diabetologia source
• Not checked yetcites [45] Foretz, 2014, Metformin: from mechanisms of action to therapies, Cell Metab source

In the paper

“The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin), and improving endothelial dysfunction, probably through an effect on the mitochondria.”

In the paper

“however, metformin did not change the frequency of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) fetuses or of hypoglycemia and preeclampsia(75).”

What the sources say

• Not checked yetcites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

In the paper

“The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin), and improving endothelial dysfunction, probably through an effect on the mitochondria.”

In the paper

“an increased insulin suppression of endogenous glucose production by the liver(44, 45)”

What the sources say

• Not checked yetcites [44] Natali, 2006, Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review, Diabetologia source
• Not checked yetcites [45] Foretz, 2014, Metformin: from mechanisms of action to therapies, Cell Metab source

In the paper

“The good news for obstetricians is that preeclampsia has the potential to be added to this list (20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“Gui et al.(75) published a systematic review and meta-analysis in which metformin was shown to be superior to insulin in reducing maternal weight gain during pregnancy as well as in the frequency of gestational hypertension (Figure 5a,); however, metformin did not change the frequency of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) fetuses or of hypoglycemia and preeclampsia(”

What the sources say

• Not checked yetcites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

In the paper

“a decreased in hepatic glucose production by suppression of gluconeogenesis(44, 45)”

What the sources say

• Not checked yetcites [44] Natali, 2006, Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review, Diabetologia source
• Not checked yetcites [45] Foretz, 2014, Metformin: from mechanisms of action to therapies, Cell Metab source

In the paper

“We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (primary endpoint), but did decrease the frequency of preeclampsia (a secondary endpoint).”

In the paper

“experimental studies, as well as observations in randomized clinical trials, suggest that metformin could have a place in the treatment or prevention of preeclampsia.”

In the paper

“By far the most important mechanism is the reduction in hepatic glucose production that is considered mediated by the activation of the global energy sensor in cells, adenosine monophosphate-activated protein kinase (AMPK) (Figure 1).(46)”

What the sources say

• Not checked yetcites [46] Viollet, 2012, Cellular and molecular mechanisms of metformin: an overview, Clin Sci source

In the paper

“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“There is excessive production of sVEGFR-1 and soluble endoglin in the uterus of preeclamptic patients(121) proportional to the severity of the disease (151–153)”

What the sources say

• Not checked yetcites [121] Bujold, 2005, Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin, J Matern Fetal Neonatal Med source
• Not checked yetcites [151] Levine, 2004, Circulating angiogenic factors and the risk of preeclampsia, N Engl J Med source
• Not checked yetcites [152] Lai, 2014, Competing risks model in screening for preeclampsia by serum placental growth factor and soluble fms-like tyrosine kinase-1 at 30-33 weeks’ gestation, Fetal Diagn Ther source
• Not checked yetcites [153] Tsiakkas, 2016, Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 30-34 weeks’ gestation, Am J Obstet Gynecol source

In the paper

“The most widely known ‘toxins’ at this time are sFlt-1 (or sVEGFR-1) and soluble endoglin(118–142).”

What the sources say

• Not checked yetcites 118–142

In the paper

“By contrast, in the EMPOWaR trial, compliance was defined as ingestion of at least one tablet for at least 29% of the days between randomization and delivery, and only 67% of women fulfilled this criterion(95).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source
• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“Suboptimal compliance in randomized trials is well known to cause negative results(97–101).”

What the sources say

• Not checked yetcites [97] Cramer, 1991
• Not checked yetcites [98] Cramer, 2002, Effect of partial compliance on cardiovascular medication effectiveness, Heart source
• Not checked yetcites [99] Cramer, 2003, Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes, Value Health source
• Not checked yetcites [100] Cramer, 2008, Medication compliance and persistence: terminology and definitions, Value Health source
• Not checked yetcites [101] Shingler, 2014, Treatment preference, adherence and outcomes in patients with cancer: literature review and development of a theoretical model, Curr Med Res Opin source

In the paper

“It is also noteworthy that only 13% (443/3329) of eligible patients consented to participate in the EMPOWaR study, whereas 47% (400/844) of eligible women were recruited to the Fetal Medicine Foundation study, making the latter group more representative of women who meet the study’s eligibility criteria and to whom the study’s results apply.”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“In this trial, metformin had no significant effect on birth weight, maternal weight gain during gestation, preeclampsia, or combined adverse pregnancy outcomes, including miscarriage, termination of pregnancy, or fetal or neonatal death(95).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“The increase of sVEGFR-1 causes a parallel decrease of maternal plasma concentrations of PIGF in preeclampsia(119, 143–150).”

What the sources say

• Not checked yetcites [119] Chaiworapongsa, 2004, Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award, Am J Obstet Gynecol source
• Not checked yetcites [143] Chaiworapongsa, 2014, Pre-eclampsia part 1: current understanding of its pathophysiology, Nat Rev Nephrol source
• Not checked yetcites [144] Ogge, 2010, Serum and plasma determination of angiogenic and anti-angiogenic factors yield different results: the need for standardization in clinical practice, J Matern Fetal Neonatal Med source
• Not checked yetcites [145] Powers, 2010, Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies, PloS One source
• Not checked yetcites [146] Rana, 2012, Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia, Circulation source
• Not checked yetcites [147] Baltajian, 2016, Sequential plasma angiogenic factors levels in women with suspected preeclampsia, Am J Obstet Gynecol source
• Not checked yetcites [148] Karumanchi, 2016, Angiogenic factors in preeclampsia: from diagnosis to therapy, Hypertension source
• Not checked yetcites [149] Holme, 2016, In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies, Am J Obstet Gynecol source
• Not checked yetcites [150] Malshe, 2017, Angiogenic and antiangiogenic markers for prediction and risk classification of preeclampsia, Clin Obstet Gynecol source

In the paper

“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“In this trial, metformin had no significant effect on birth weight, maternal weight gain during gestation, preeclampsia, or combined adverse pregnancy outcomes, including miscarriage, termination of pregnancy, or fetal or neonatal death(95).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“In the Fetal Medicine Foundation trial, almost 80% of women took at least 50% of the total number of tablets prescribed, and 91% of those prescribed more than 2.5 g/day did so(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“The finding that metformin decreased the frequency of preeclampsia was consistent with the findings reported in a meta-analysis by Gui et al.(75) and Feng and Yang(76).”

What the sources say

• Not checked yetcites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source
• Not checked yetcites [76] Feng, 2017, Metformin: a potentially effective drug for gestational diabetes mellitus: a systematic review and meta-analysis, J Matern Fetal Neonatal Med source

In the paper

“making the latter group more representative of women who meet the study’s eligibility criteria and to whom the study’s results apply.”

In the paper

“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“In the Fetal Medicine Foundation trial, almost 80% of women took at least 50% of the total number of tablets prescribed, and 91% of those prescribed more than 2.5 g/day did so(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“In this trial, metformin had no significant effect on birth weight, maternal weight gain during gestation, preeclampsia, or combined adverse pregnancy outcomes, including miscarriage, termination of pregnancy, or fetal or neonatal death(95).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“It is also noteworthy that only 13% (443/3329) of eligible patients consented to participate in the EMPOWaR study, whereas 47% (400/844) of eligible women were recruited to the Fetal Medicine Foundation study, making the latter group more representative of women who meet the study’s eligibility criteria and to whom the study’s results apply.”

What the sources say

• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source
• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source
• Not checked yetcites [96] Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med source

In the paper

“Differences in trial design, execution and compliance are the most likely explanations for the contradictory results obtained in these two randomized clinical trials from the United Kingdom.”

In the paper

“In this trial, metformin had no significant effect on birth weight, maternal weight gain during gestation, preeclampsia, or combined adverse pregnancy outcomes, including miscarriage, termination of pregnancy, or fetal or neonatal death(95).”

What the sources say

• Not checked yetcites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

In the paper

“The tissues of women with preeclampsia showed central disruption in mitochondrial morphology and changes in the Golgi apparatus, endoplasmic reticulum, and small, unidentified microvesicles, and these mitochondrial changes were not limited to uterine tissues, thus implying that mitochondrial dysfunction was a systemic disorder.”

What the sources say

• Not checked yetcites [198] Shanklin, 1990, Ultrastructural aspects of preeclampsia: II, mitochondrial changes, Am J Obstet Gynecol source

In the paper

“Brownfoot et al.(20) from the Translational Obstetrics Group of the Department of Obstetrics and Gynecology, Mercy Hospital for Women, at the University of Melbourne, Heidelberg, Victoria, Australia, reported that metformin reduced the production of soluble fms-like tyrosine kinase-1 (sFlt-1, also known as soluble vascular endothelial growth factor receptor 1 or sVEGFR-1) and soluble endoglin (sEN”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“and 4) increased mitochondrial respiration in the presence of Complex I substrates(208).”

What the sources say

• Not checked yetcites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

In the paper

“2) a five-fold decrease in the mitochondrial transcription factor (TFAM)-A;”

What the sources say

• Not checked yetcites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

In the paper

“However, the most persuasive evidence that metformin has a vascular effect is the finding that it reverses the impairment of vascular relaxation induced by incubating the maternal blood vessels obtained from the omentum at the time of cesarean delivery with placental conditioned media of patients with preeclampsia(20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“aside from its effects on sterile inflammation and iron metabolism, miR-210 also modulates mitochondrial function.”

In the paper

“Metformin also decreased the expression of vascular cell adhesion molecule 1 (VCAM1), expressed by endothelial cells that are dysfunctional or have been stimulated by incubation with tumor necrosis factor alpha (TNF-α), a cytokine increased in the circulation of patients with preeclampsia(190–195).”

What the sources say

• Not checked yetcites [190] Vince, 1995, Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia, Br J Obstet Gynaecol source
• Not checked yetcites [191] Bartha, 2001, The relationships between leptin and inflammatory cytokines in women with pre-eclampsia, BJOG
• Not checked yetcites [192] Velzing-Aarts, 2002, High serum interleukin-8 levels in afro-caribbean women with pre-eclampsia: relations with tumor necrosis factor-alpha, duffy negative phenotype and von Willebrand factor, Am j reprod immunol source
• Not checked yetcites [193] Visser, 2002, Soluble tumor necrosis factor receptor II and soluble cell adhesion molecule 1 as markers of tumor necrosis factor-alpha release in preeclampsia, Acta Obstet Gynecol Scand
• Not checked yetcites [194] Tosun, 2010, Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia, J Matern Fetal Neonatal Med source
• Not checked yetcites [195] Szarka, 2010, Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array, BMC Immunol source

In the paper

“Torbergsen et al.(196) first suggested that mitochondria might be involved in the pathogenesis of preeclampsia based upon the high frequency of preeclampsia in a family suffering from mitochondrial dysfunction.”

What the sources say

• Not checked yetcites [196] Torbergsen, 1989, Pre-eclampsia: a mitochondrial disease?, Acta Obstet Gynecol Scand source

In the paper

“The laboratory of Professor Leslie Myatt provided evidence that placental mitochondrial dysfunction is mediated, at least in part, by miR-210 by demonstrating that mitochondrial complexes I, III, and IV decreased in preeclampsia, along with a decrease in the iron-sulfur cluster scaffold homologue (ISCU)(207).”

What the sources say

• Not checked yetcites [207] Muralimanoharan, 2012, MIR-210 modulates mitochondrial respiration in placenta with preeclampsia, Placenta source

In the paper

“3) a 1.5-fold increase of the relative placental mitochondrial DNA copy number;”

What the sources say

• Not checked yetcites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

In the paper

“Overall, Brownfoot et al.’s findings suggest that metformin may have a role in the prevention of preeclampsia through its effect on cell metabolism, on the anti-angiogenic state, and, most likely, on other processes associated with this obstetrical syndrome(20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“For example, if sVEGFR-1 is administered to rats using an adenovirus vector, the animals develop hypertension, proteinuria, and glomerular endotheliosis(180).”

What the sources say

• Not checked yetcites [180] Maynard, 2003, Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia, J Clin Invest source

In the paper

“the median maternal whole blood mitochondrial DNA copy number was higher in women with preeclampsia than in those who experienced a normal pregnancy (p<0.001)(201)”

What the sources say

• Not checked yetcites [201] Qiu, 2012, A case-control study of maternal blood mitochondrial DNA copy number and preeclampsia risk, Int J Mol Epidemiol Genet

In the paper

“Using bioinformatic tools, differentially expressed proteins in this study were identified as participating in many critical processes of preeclampsia, such as reactive oxygen species generation, apoptosis, fatty acid oxidation, respiratory chain function, and the tricarboxylic acid cycle(200)”

What the sources say

• Not checked yetcites [200] Shi, 2013, Comparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia, PloS One source

In the paper

“An increase in the P/O ratio (a measure for how much ATP is synthesized per 2 electrons transferred to oxygen) was observed in both early and late preeclampsia.”

What the sources say

• Not checked yetcites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

In the paper

“In 1990, Shanklin and Sibai(198) reported that mitochondria from small vessels, myometrial smooth muscle, myometrial interstitial cells, circulating leukocytes, epidermal and dermal cells, and hepatocytes in women with preeclampsia all had morphologic changes that were quite different from those seen in normal pregnancies(198).”

What the sources say

• Not checked yetcites [198] Shanklin, 1990, Ultrastructural aspects of preeclampsia: II, mitochondrial changes, Am J Obstet Gynecol source

In the paper

“similar results have been obtained in mice(141).”

What the sources say

• Not checked yetcites [141] Szalai, 2015, Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice, PloS One source

In the paper

“This condition is indistinguishable from the HELLP syndrome observed in humans(181–184).”

What the sources say

• Not checked yetcites [181] Weinstein, 1982, Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy, Am J Obstet Gynecol source
• Not checked yetcites [182] Romero, 1988, Clinical significance of liver dysfunction in pregnancy-induced hypertension, Am J Perinatol source
• Not checked yetcites [183] Abildgaard, 2013, Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review, Eur J Obstet Gynecol Reprod Biol source
• Not checked yetcites [184] Szabo, 2015, Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome, Pathol Oncol Res source

In the paper

“suggesting that an influx of mitochondrial DNA into the maternal circulation may act as a danger signal/alarmin responsible for the sterile (absence of infection) intravascular inflammatory processes of this condition(202, 203)”

What the sources say

• Not checked yetcites [202] Bonney, 2007, Preeclampsia: a view through the danger model, J Reprod Immunol source
• Not checked yetcites [203] Mando, 2014, Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia, Am J Physiol Endocrinol Metab source

In the paper

“Comparative proteomics analysis of placental mitochondria in normal patients and those with preeclampsia has shown up-regulation of four proteins and down-regulation of 22 proteins.”

What the sources say

• Not checked yetcites [200] Shi, 2013, Comparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia, PloS One source

In the paper

“That same year, Berkowitz et al.(199) reported a case of abnormal mitochondrial morphology observed in an endomyocardial biopsy obtained from a 20-year-old nulliparous woman, known to have mitochondrial myopathy, who developed severe preeclampsia(199).”

What the sources say

• Not checked yetcites [199] Berkowitz, 1990, Mitochondrial myopathy and preeclampsia associated with pregnancy, Am J Obstet Gynecol source

In the paper

“Metformin also abrogated the reduction of angiogenic sprouting induced in human omental vessel explants by incubation with VEGFR-1 (Figure 7)(20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“Additionally, if sVEGFR1 and soluble endoglin are given to pregnant rats, the animals not only develop preeclampsia but also liver dysfunction, thrombocytopenia, and intrauterine growth restriction(124); similar results have been obtained in mice(141).”

What the sources say

• Not checked yetcites [124] Venkatesha, 2006, Soluble endoglin contributes to the pathogenesis of preeclampsia, Nat Med source

In the paper

“Collectively, this evidence, coupled with the conduction of workshop recently held by the International Federation of Placental Associations on the role of mitochondria in placental function(209), suggests that mitochondrial dysfunction plays a major role in the pathogenesis of preeclampsia.”

What the sources say

• Not checked yetcites [209] Bianco-Miotto, 2016, IFPA meeting 2015 workshop report I: placental mitochondrial function, transport systems and epigenetics, Placenta source

In the paper

“The administration of sFlt-1 (or sVEGFR-1) and/or soluble endoglin to animals produces changes characteristic of preeclampsia.”

In the paper

“Given the evidence that metformin acts through the mitochondrial electron transport chain (ETC) by inhibiting complex I(46, 210–212) (Figure 8)”

What the sources say

• Not checked yetcites [46] Viollet, 2012, Cellular and molecular mechanisms of metformin: an overview, Clin Sci source
• Not checked yetcites [210] Owen, 2000, Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain, Biochem J source
• Not checked yetcites [211] Hur, 2015, New mechanisms of metformin action: Focusing on mitochondria and the gut, J Diabetes Investig source
• Not checked yetcites [212] Madiraju, 2014, Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, Nature source

In the paper

“Disorders in nutrient-sensing pathways may lead to fetal growth disorders, and studies by Professors Powell and Jansson have provided unique insights into nutrient sensing by the human placenta(225–227).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source
• Not checked yetcites [227] Rosario, 2013, Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells, J Physiol source

In the paper

“However, Brownfoot et al.(20) demonstrated that other electron transport chain inhibitors (antimycin and rotenone) blocked secretion of sFlt-1 and soluble endoglin, suggesting that the electron transport chain is the major effector of the benefits of metformin.”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“The activation of mTOR is positively correlated with the first-trimester maternal body mass index, linking maternal over-nutrition and nutritient-sensing by the placenta; while its expression is down-regulated when fetal growth is restricted (in both animal models and humans).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

In the paper

“A family of molecules that are the mechanistic target of the rapamycin (mTOR) complex has been attributed a major role in the biology of cell metabolism, growth, longevity, and even preterm birth(230–236).”

What the sources say

• Not checked yetcites [230] Zoncu, 2011, mTOR: from growth signal integration to cancer, diabetes and ageing, Nat Rev Mol Cell Biol source
• Not checked yetcites [231] Hirota, 2011, Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice, Proc Natl Acad Sci U S A source
• Not checked yetcites [232] Shimobayashi, 2014, Making new contacts: the mTOR network in metabolism and signalling crosstalk, Nat Rev Mol Cell Biol source
• Not checked yetcites [233] Kim, 2015, MTOR: a pharmacologic target for autophagy regulation, J Clin Invest source
• Not checked yetcites [234] Deng, 2016, P53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing, J Clin Invest source
• Not checked yetcites [235] Kennedy, 2016, The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging, Cell Metab source
• Not checked yetcites [236] Xie, 2016, MTOR inhibitors in cancer therapy, F1000Res source

In the paper

“There are also changes in these pathways in cases of fetal growth restriction caused by maternal starvation or impaired placentation where there is down-regulation of placental nutrient transport(225, 226).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

In the paper

“mTOR regulates two key amino-acid transport systems (A and L).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

In the paper

“For example, down-regulation of mechanistic target of rapamycin (mTOR) in the placenta has been reported in SGA/growth-restricted fetuses (see Figure 11)(226).”

What the sources say

• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

In the paper

“Rapamycin prolongs lifespan by inhibiting the effects of mTOR.”

What the sources say

• Not checked yetcites [238] Xu, 2014, MTOR signaling from cellular senescence to organismal aging, Aging Dis
• Not checked yetcites [239] Wei, 2015, The role of mitochondria in mTOR-regulated longevity, Biol Rev Camb Philos Soc source

In the paper

“Upon activation, the serine/threonine kinases activate a cascade of intracellular processes involving the mitochondria and the nucleus of the cell to promote cellular growth and, to a certain extent, aging.”

In the paper

“Indeed, succinate in the absence of metformin appears to have no effect(20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“The reduction in the secretion of anti-angiogenic factors by metformin was reversed when succinate (whose metabolism via complex II bypasses complex I) was used as an electron source(20).”

What the sources say

• Not checked yetcites [20] Brownfoot, 2016, Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction, Am J Obstet Gynecol source

In the paper

“Similarly, when the placenta senses an excess of nutrients (as in obesity, diabetes, or other metabolic disorders) mTOR activation and fetal growth acceleration may be expected to occur.”

In the paper

“The mTOR Akt-mTOR-HIF-1α signaling pathway also affects placental angiogenesis by its ability to increase VEGF and endoglin expression in response to hypoxia in a trophoblast cell line(241).”

What the sources say

• Not checked yetcites [241] Fujita, 2010, Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line, J Endocrinol source

In the paper

“while its expression is down-regulated when fetal growth is restricted (in both animal models and humans).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

In the paper

“Each of these nutritient-sensing pathways is present in the human placenta(225–227).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source
• Not checked yetcites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source
• Not checked yetcites [227] Rosario, 2013, Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells, J Physiol source

In the paper

“mTOR is a major human nutrient-sensing receptor in the placenta(225).”

What the sources say

• Not checked yetcites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source

In the paper

“In addition, rare side-effects such as mild erythema and decreased vitamin B12 absorption have been associated with long-term administration(252).”

What the sources say

• Not checked yetcites [252] Lautatzis, 2013, Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review, Metabolism source

In the paper

“Animal experiments have elucidated the mechanisms underlying these epidemiological findings, i.e., suppression of cancer stem cells(264);”

What the sources say

• Not checked yetcites [264] Vazquez-Martin, 2011, Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions, Drug Resist Updat source

In the paper

“Similarly, no excess of fetal or neonatal complications could be demonstrated when the administration of metformin was compared to glyburide and insulin(249).”

What the sources say

• Not checked yetcites [249] Nicholson, 2011, Oral hypoglycaemic agents during pregnancy: the evidence for effectiveness and safety, Best Pract Res Clin Obstet Gynaecol source

In the paper

“metformin was shown to extend longevity in worms(2) and mice(3) (although not in Drosophila(275)).”

What the sources say

• Not checked yetcites [3] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

In the paper

“Several meta-analyses that studied the teratogenic effect of metformin on embryonic development found that this drug carries no increased risk for congenital malformations(245, 246)”

What the sources say

• Not checked yetcites [245] Cassina, 2014, First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis, Hum Reprod Update source
• Not checked yetcites [246] Gilbert, 2006, Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis, Fertil steril source

In the paper

“Maternal side-effects reported with the use of metformin are mainly gastro-intestinal, i.e., nausea and diarrhea(248).”

What the sources say

• Not checked yetcites [248] Nestler, 2008, Metformin for the treatment of the polycystic ovary syndrome, N Engl J Med source

In the paper

“Originally introduced for the treatment of diabetes, metformin is now gaining attention as a potential anti-cancer agent (7–10) (Figure 1).”

What the sources say

• Not checked yetcites [7] Zhang, 2014, Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis, Am J Epidemiol source
• Not checked yetcites [8] Franciosi, 2013, Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review, PloS One source
• Not checked yetcites [9] Wang, 2014, Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis, Diabetes Res Clin Pract source
• Not checked yetcites [10] Wu, 2015, Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies, Scientific Rep source

In the paper

“and interference with glucose(266), protein(267, 268), and lipid(269) metabolism of the neoplastic cells.”

What the sources say

• Not checked yetcites [266] Shackelford, 2009, The LKB1-AMPK pathway: metabolism and growth control in tumour suppression, Nat Rev Cancer source
• Not checked yetcites [267] Green, 2010, The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation, Blood source
• Not checked yetcites [268] Zakikhani, 2006, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells, Cancer Res source

In the paper

“Metformin exerts many of its growth inhibitory and anti-neoplastic effects through the nuclear pore complex and acyl-CoA dehydrogensase family member-10 (ACAD10)(278).”

What the sources say

• Not checked yetcites [278] Wu, 2016, An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer, Cell source

In the paper

“Indeed, an ex vivo dually perfused human placental lobule demonstrated the rapid transfer of metformin from maternal to fetal circulation with a lag time of 1.7±0.28 minutes similarly observed in women with normal pregnancies and those diagnosed with gestational diabetes mellitus(242).”

What the sources say

• Not checked yetcites [242] Nanovskaya, 2006, Transfer of metformin across the dually perfused human placental lobule, Am J Obstet Gynecol source

In the paper

“In vivo studies reported the detection of metformin in the umbilical cord blood of neonates from women with polycystic ovarian syndrome who were treated with metformin throughout gestation(243, 244).”

What the sources say

• Not checked yetcites [243] Charles, 2004, Metformin crosses the placenta: a modulator for fetal insulin resistance?, Br Med J
• Not checked yetcites [244] Vanky, 2005, Placental passage of metformin in women with polycystic ovary syndrome, Fertil Steril source

In the paper

“Metformin has now been found to target several age-related pathways(3, 276, 277)”

What the sources say

• Not checked yetcites [3] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source
• Not checked yetcites [276] Lopez-Otin, 2016, Metabolic control of longevity, Cell source
• Not checked yetcites [277] Novelle, 2016, Metformin: a hopeful promise in aging research, Cold Spring Harbor Perspect Med source

In the paper

“this finding has subsequently been confirmed in several other studies(7–10).”

What the sources say

• Not checked yetcites [7] Zhang, 2014, Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis, Am J Epidemiol source
• Not checked yetcites [8] Franciosi, 2013, Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review, PloS One source
• Not checked yetcites [9] Wang, 2014, Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis, Diabetes Res Clin Pract source
• Not checked yetcites [10] Wu, 2015, Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies, Scientific Rep source

In the paper

“This epidemiologic evidence has coalesced with experimental work in animals(256–263).”

What the sources say

• Not checked yetcites [256] Mohammed, 2013, Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling, Transl Oncol source
• Not checked yetcites [257] Anisimov, 2005, Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice, Exp gerontol source
• Not checked yetcites [258] Anisimov, 2014, Do metformin a real anticarcinogen? A critical reappraisal of experimental data, Ann Transl Med
• Not checked yetcites [259] Afzal, 2012, Preventive effect of Metformin against N-nitrosodiethylamine-initiated hepatocellular carcinoma in rats, Saudi Pharm J source
• Not checked yetcites [260] Anisimov, 2011, If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice, Aging source
• Not checked yetcites [261] Huang, 2008, Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice, Biochem J source
• Not checked yetcites [262] Tajima, 2013, Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice, Am J Physiol Endocrinol Metab source
• Not checked yetcites [263] Tomimoto, 2008, Metformin suppresses intestinal polyp growth in ApcMin/+ mice, Cancer Sci source

In the paper

“inhibition of epithelial-to-mesenchymal transition(265), (which is implicated in metastasis);”

What the sources say

• Not checked yetcites [265] Cufi, 2010, Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis, Cell cycle source

In the paper

“The rate of hypoglycemia is lower than that reported with insulin(79).”

What the sources say

• Not checked yetcites [79] Spaulonci, 2013, Randomized trial of metformin vs insulin in the management of gestational diabetes, Am J Obstet Gynecol source

In the paper

“similar observatons werealso found by targeting mitochondrial genes(274)”

What the sources say

• Not checked yetcites [274] Dillin, 2002, Rates of behavior and aging specified by mitochondrial function during development, Science source

In the paper

“metformin was shown to extend longevity in worms(2) and mice(3) (although not in Drosophila(275)).”

What the sources say

• Not checked yetcites [2] Cabreiro, 2013, Metformin retards aging in C elegans by altering microbial folate and methionine metabolism, Cell source

In the paper

“There is further evidence that metformin may also have an adjunctive effect in patients receiving chemotherapy(270), and there are now more than 100 ongoing trials”

What the sources say

• Not checked yetcites [270] Jiralerspong, 2009, Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer, J Clin Oncol source

In the paper

“evidence that metformin may also have an adjunctive effect in patients receiving chemotherapy(270)”

What the sources say

• Not checked yetcites [270] Jiralerspong, 2009, Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer, J Clin Oncol source

In the paper

“Similar concentrations of metformin in the umbilical artery and umbilical vein suggest negligible metformin metabolism by the fetus (244).”

What the sources say

• Not checked yetcites [244] Vanky, 2005, Placental passage of metformin in women with polycystic ovary syndrome, Fertil Steril source

In the paper

“an unbiased search for genes that extend lifespan has identified a disproportionate number of genes that function in mitochondrial metabolism(273)”

What the sources say

• Not checked yetcites [273] Lee, 2003, A systematic RNAi screen identifies a critical role for mitochondria in C elegans longevity, Nature Genet source

In the paper

“The first observation that metformin might reduce the risk of cancer was made in a population-based case-control study of type 2 diabetic patients treated with metformin(253).”

What the sources say

• Not checked yetcites [253] Evans, 2005, Metformin and reduced risk of cancer in diabetic patients, BMJ source