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

“Butalia et al.(77) reported that, compared to insulin, metformin significantly decreased the frequency of neonatal hypoglycemia, LGA neonates, and admissions to a neonatal intensive care unit (Figure 5b,)(56, 72–74, 77–83).”

What the sources say

• Not checked yetcites [77] Butalia, 2017, Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis, Diabetic Med source

In the paper

“There is considerable evidence suggesting that this agent is safe during pregnancy.”

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

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

In the paper

“Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by mTOR.”

In the paper

“Originally introduced in clinical practice as an anti-diabetic agent, its role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and more recently, 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

“Gui et al.(75) suggested that metformin reduced the rate of gestational hypertension because of its effects on endothelial function and its decrease in the production of reactive oxygen species, the two mechanisms implicated in the pathophysiology of preeclampsia(84–94).”

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 [84] Rodgers, 1988, Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells, Am J Obstet Gynecol source
• Not checked yetcites [85] Roberts, 1989, Preeclampsia: an endothelial cell disorder, Am J Obstet Gynecol source
• Not checked yetcites [86] Myatt, 2009, Vascular biology of preeclampsia, J Thromb Haemost source
• Not checked yetcites [87] Myatt, 2000, Oxidative stress causes vascular dysfunction in the placenta, J Matern Fetal Med
• Not checked yetcites [88] Hubel, 1996, Decreased transferrin and increased transferrin saturation in sera of women with preeclampsia: implications for oxidative stress, Am J Obstet Gynecol source
• Not checked yetcites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source
• Not checked yetcites [90] Burton, 2004, Placental oxidative stress: from miscarriage to preeclampsia, J Soc Gynecol Investig source
• Not checked yetcites [91] Burton, 2009, Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia, Placenta source
• Not checked yetcites [92] Myatt, 2010, Review: reactive oxygen and nitrogen species and functional adaptation of the placenta, Placenta source

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

“Soluble endoglin is a cell surface co-receptor for transforming growth factor (TGF)-β1, which blocks TGF-β1–mediated activation of endothelial nitric oxide synthase (eNOS) and promotes vasorelaxation(124).”

What the sources say

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

In the paper

“that causes maternal plasma concentrations of sVEGFR-1 and soluble endoglin to increase before preeclampsia is diagnosed, making them potential biomarkers for the disease(111, 120, 128, 129, 132, 133, 137, 138, 154–179).”

What the sources say

• Not checked yetcites [111] Chaiworapongsa, 2014, Pre-eclampsia part 2: prediction, prevention and management, Nat Rev Nephrol source
• Not checked yetcites [120] Chaiworapongsa, 2005, Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia, J Matern Fetal Neonatal Med source
• Not checked yetcites [128] Erez, 2008, The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age, J Matern Fetal Neonatal Med source

In the paper

“Importantly, transfection of cells with miR-210 resulted in a significant reduction in oxygen consumption by mitochondria, mitochondrial respiratory deficiency, and production of ROS(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

“Torbergsen et al. suggested that these women developed preeclampsia because their dysfunctional mitochondria could not meet the increased energy demands of pregnancy, and the failure of adequate cellular energy production led to an accumulation of ADP, which is able to mediate most of the changes seen in preeclampsia(89, 197)”

What the sources say

• Not checked yetcites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source
• Not checked yetcites [197] Masoura, 2015, The involvement of uric acid in the pathogenesis of preeclampsia, Curr Hypertens Rev source

In the paper

“while both early and late preeclampsia are associated with an elevated P/O ratio(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

“Six of 10 women with a mitochondrial disease had at least one pregnancy complicated by preeclampsia or eclampsia, whereas none had been hypertensive in the non-pregnant state.”

What the sources say

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

In the paper

“Although the emphasis on the toxic factors produced by an ischemic placenta has been on the balance between angiogenic and anti-angiogenic factors, evidence now suggests that cytokines, such as TNF-α and IL-10, are altered in early and late preeclampsia, and the changes correlate with the type of histopathological changes in the placenta(185).”

What the sources say

• Not checked yetcites [185] Weel, 2016, Association between placental lesions, cytokines and angiogenic factors in pregnant women with preeclampsia, PloS One source

In the paper

“Thus, early-onset preeclampsia is associated with mitochondrial activation, up-regulation of OPA-1, active DNA replication (resulting from a high respiration rate), and TFAM down-regulation, while both early and late preeclampsia are associated with an elevated P/O ratio(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

“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

“Women with early-onset preeclampsia had 1) a two-fold increase in the mRNA expression of OPA (optic atrophy)-1 and a three-fold increase in OPA-1 protein expression (cleaved and uncleaved forms) in patients with early-onset 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

“the report also suggested that metformin regulates these anti-angiogenic factors at the level of the mitochondria.”

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

“ADP is a vasoconstrictor, causes platelet aggregation, and breaks down to uric acid.”

What the sources say

• Not checked yetcites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source
• Not checked yetcites [197] Masoura, 2015, The involvement of uric acid in the pathogenesis of preeclampsia, Curr Hypertens Rev source

In the paper

“the placentas of patients with preeclampsia(204), as well as those from pregnancies with preeclampsia and SGA(205), overexpress the microRNA (miR)-210”

What the sources say

• Not checked yetcites [204] Zhu, 2009, Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies, Am J Obstet Gynecol source
• Not checked yetcites [205] Pineles, 2007, Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia, Am J Obstet Gynecol source

In the paper

“Additionally, it was demonstrated that miR-210 was induced by hypoxia, and RNA interference knockdown resulted in autophagosomal and siderosomal iron accumulation, implicating siderosis or interstitial trophoblasts as mechanisms in preeclampsia and SGA(206)”

What the sources say

• Not checked yetcites [206] Lee, 2011, MiR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies, Am J Pathol source

In the paper

“This signaling system is highly expressed in the syncytiotrophoblast, and its activity is regulated by glucose and amino-acid concentrations(226, 227, 240).”

What the sources say

• 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
• Not checked yetcites [240] Lager, 2012, Regulation of nutrient transport across the placenta, J Pregnancy

In the paper

“Nutrient sensing occurs through several pathways(225), the most important of which are: the AMPK pathway, which is a global energy sensor in cells;glycogen synthase 3 (GSK-3), which acts as a glucose sensor;the hexose-amino signaling pathway, which depends on the availability of nutrients such as glucose, glutamine, and acetyl-CoA;the amino-acid response signal transduction pathway, which is activ”

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

“However, succinate is also an inhibitor of HIF-1α(213), which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia(214, 215)”

What the sources say

• Not checked yetcites [213] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source
• Not checked yetcites [214] Kanasaki, 2008, Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia, Nature source
• Not checked yetcites [215] Tal, 2012, The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis, Biol Reprod source

In the paper

“Rapamycin acts by interacting with a family of TOR molecules that is highly-conserved functionally and evolutionarily from yeast to humans, and it contains two multiprotein complexes that are functionally and structurally different: the first, mTORC1, is rapamycin-sensitive; and the second, mTORC2, is rapamycin-resistant(237).”

What the sources say

• Not checked yetcites [237] Aylett, 2016, Architecture of human mTOR complex 1, Science source

In the paper

“Nutrient sensing is a crucial requirement for fetal development.”

In the paper

“Brownfoot et al.(20) found that metformin can improve endothelial dysfunction, reduce the expression of vascular adhesion molecule 1 mRNA induced by TNFα, and improve whole-blood vessel angiogenesis impaired by sFlt-1 or sVEGFR-1.”

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

“Rapamycin can also prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.”

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

“Both complexes control cell growth and metabolism in response to the availability of nutrients, energy, and growth factors.”

What the sources say

• Not checked yetcites [237] Aylett, 2016, Architecture of human mTOR complex 1, Science source

In the paper

“mTOR has key properties in the placenta(225, 226) that include its activation by insulin, IGF-1, and leptin, and its inhibition by cortisol.”

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

“The key structure in the placenta responsible for nutritient sensing is the syncytiotrophoblast, which covers the villous tree and is in direct contact with the maternal blood in the intervillous space.”

In the paper

“The changes in the mitochondrial function in preeclampsia suggest there are perturbations in the cellular energy balance of patients with this syndrome that affect cell growth and division (especially in the placenta and the fetus); all are modified by metformin.”

In the paper

“and is currently classified as category B in the United States and as category C in Australia (247, 248).”

What the sources say

• Not checked yetcites [247] Gray, 2017, The emerging role of metformin in gestational diabetes mellitus, Diabetes Obes Metab source
• Not checked yetcites [248] Nestler, 2008, Metformin for the treatment of the polycystic ovary syndrome, N Engl J Med source

In the paper

“Nucleocytoplasmic shuttling regulates mTORC activity, an effect that can be reversed by RNA silencing.”

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

“Those who were exposed to metformin during fetal life had a larger upper arm circumference and bigger subscapular skin folds and biceps, suggesting a better fat distribution than children exposed to insulin(251).”

What the sources say

• Not checked yetcites [251] Rowan, 2011, Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age, Diabetes Care source

In the paper

“Metformin has a molecular weight of 129 dalton, and it crosses the placenta in direct diffusion without affecting the facilitated transfer of glucose(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 a meta-analysis(255), metformin-treated diabetic patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index(255).”

What the sources say

• Not checked yetcites [255] Gandini, 2014, Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders, Cancer Prev Res source

In the paper

“Moreover, there were no differences in fat measurements, total fat mass, and percentage of body fat(251).”

What the sources say

• Not checked yetcites [251] Rowan, 2011, Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age, Diabetes Care source

In the paper

“Metformin, long known to be an herbal medicine, has evolved from its use as a popular treatment for diabetes into a drug with a significantly wider array of beneficial effects ranging from cancer treatment to extending longevity, as well as, in our field, gestational hypertension and preeclampsia in obese women.”

In the paper

“By preventing access to the nucleus, RagC becomes incapable of stimulating mTORC1 and, therefore, stimulates cellular growth (Figure 12)(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