Expert ReviewMetformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity
Section snippets
Metformin: from the pharaohs to the present
Metformin (dimethylbiguanide hydrochloride) is a constituent of many herbal remedies, and the Ebers Papyrus, written in 1500 BCE,22 records its use in Egypt since the time of the Pharaohs (Figure 2). In Europe, herbal remedies derived from the plant Galega officinalis (Figure 3) containing metformin have been prescribed to treat polyuria and other symptoms of diabetes mellitus since the Middle Ages,22, 23, 24 but it was not until the early 1900s that guanidine was identified as the organic base
The role of angiogenic and antiangiogenic factors in the genesis of preeclampsia
For more than 100 years, preeclampsia was thought to be caused by the release of “toxic factors” from an ischemic placenta, hence, the name “toxemia.”102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117 The most widely known “toxins” at this time are soluble fms-like tyrosine kinase-1 (sFlt-1 or soluble vascular endothelial growth factor receptor 1 [sVEGFR-1]) and soluble endoglin.118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,
Nutrient sensing: key for the survival of all living forms
“Cell growth and division are the two most fundamental features of life.”220 All organisms must be able to detect nutrient levels in their environment to coordinate growth and development. This is true of bacteria that must choose whether to grow or to remain stationary, and, in the case of motile bacteria, to determine in which direction to move, depending on the availability of nutrients. Bacteria evolved specific chemoreceptors for this purpose that coordinate information received from the
Safety of metformin during pregnancy
Metformin has a molecular weight of 129 Daltons and crosses the placenta by direct diffusion without affecting the facilitated transfer of glucose.242 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 In vivo studies reported the detection of metformin in the
A role for metformin in cancer and aging
Originally introduced for the treatment of diabetes mellitus, metformin is now gaining attention as a potential anticancer agent (Figure 1).7, 8, 9, 10 The first observation that metformin might reduce the risk of cancer was made in a population-based case-control study of patients with type 2 diabetes who were treated with metformin.253 A cohort study of type 2 diabetic patients, newly treated with metformin and later followed, reported that the frequency of cancer was significantly lower in
Conclusion
Metformin, long known to be an herbal medicine, has evolved from its use as a popular treatment for diabetes mellitus into a drug with a significantly wider array of beneficial effects that range from cancer treatment to extending longevity and, in our field, gestational hypertension and preeclampsia in obese women. Current evidence suggests that metformin’s wide-ranging beneficial effects are mediated by at least 2 primary mechanisms: suppression of intracellular metabolic activity of
References (278)
- et al.
Metformin retards aging in C elegans by altering microbial folate and methionine metabolism
Cell
(2013) - et al.
Metformin as a tool to target aging
Cell Metab
(2016) - et al.
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
(2014) - et al.
Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients
Atherosclerosis
(2015) - et al.
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
(2016) Studies in the metabolic changes induced by administration of guanidine bases
J Biol Chem
(1918)- et al.
Metformin: from mechanisms of action to therapies
Cell Metab
(2014) - et al.
Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin
Am J Obstet Gynecol
(1997) - et al.
Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome
Fertil Steril
(2002) - et al.
Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and post partum
Lancet Diabetes Endocrinol
(2016)
Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial
Diabetes Res Clin Pract
Randomized trial of metformin vs insulin in the management of gestational diabetes
Am J Obstet Gynecol
Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial
Diabetes Res Clin Pract
Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells
Am J Obstet Gynecol
Preeclampsia: an endothelial cell disorder
Am J Obstet Gynecol
Vascular biology of preeclampsia
J Thromb Haemost
Hyperuricemia and xanthine oxidase in preeclampsia, revisited
Am J Obstet Gynecol
Review: reactive oxygen and nitrogen species and functional adaptation of the placenta
Placenta
Oxidative stress
Best Pract Res Clin Obstet Gynaecol
Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development
Am J Obstet Gynecol
Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial
Lancet Diabetes Endocrinol
Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes
Value Health
Medication compliance and persistence: terminology and definitions
Value Health
Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1
PloS One
Metformin improves healthspan and lifespan in mice
Nat Commun
Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2
Proc Natl Acad Sci U S A
Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis
Am J Epidemiol
Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review
PloS One
Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies
Scientific Rep
Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis
Clin Invest Med
Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis
Gynecol Endocrinol
Is metformin therapy for polycystic ovary syndrome safe during pregnancy?
Basic Clin Pharmacol toxicol
Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review
Ann Intern Med
Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis
J Immunol
Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis
JAMA Neurol
Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism
Diabetes
Systematic review: preventive and therapeutic applications of metformin in liver disease
World J Hepatol
Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy
Obstet Gynecol
The blooming of the French lilac
J Clin Invest
Metformin
N Engl J Med
Metformin: its botanical background
Pract Diabetes Int
Pharmacology and mode of action of the hypoglycaemic guanidine derivatives
Pharmacology of galegin
Arch Expll Path Pharm
[Sur les propietes hypoglycemiantes du sulfate de galegine.]
Bull Soc Chim Biol Paris
Biguanides
Diabetologia
[Recherches sur le role du pancreas dans l’assimilation nutritive.]
Arch Int Physiol
Pancreatic extracts in the treatment of diabetes mellitus
Can Med Assoc J
[Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage)]
Therapie
Lactic acidosis and phenformin hydrochloride
JAMA
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This work was supported, in part, by the Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C.
The authors report no conflict of interest.