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

Abstract

Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non-diabetic, pregnant women to prevent macrosomia. 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 (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. 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 rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin.

Keywords: fms-like tyrosine kinase-1 (sFlt-1); insulin resistance; large for gestational age (LGA); mTOR; macrosomia; mitochondria; nutritional sensing; obesity; placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1).

Published by Elsevier Inc.

Figures

Figure 1. Different effects of metformin and its signaling pathways

Metformin reduces insulin resistance, secretion, glucose blood levels, inflammation, and angiogenesis as well as reduction in cell growth and metabolism that mediates its anti-tumor activity. These effects are regulated by both AMPK-dependent or -independent mechanisms that lead to the inhibition of mTOR signaling. (Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, 5′ adenosine monophosphate-activated protein kinase; IGF, Insulin-like growth factor; EGF, Epidermal growth factor; FAS, fatty acid synthase; PAI-1, plasminogen-activator inhibitor-1; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; TSC2, tuberous sclerosis 2; mTOR, mechanistic target of rapamycin; VEGF, vascular endothelial growth factor) Reproduced with permission from Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012; 122:253-70 and http://diabetesmanager.pbworks.com/f/1255202482/metformin.JPG

Figure 2. Ebers papyrus

This document, 20 meters long, contains a collection of medical texts considered to be the most comprehensive account of the practice in Egyptian medicine. Its encyclopedic content addresses not only multiple illnesses, e.g., treatment for diabetes, but also crocodile bites, mental illness, and treatment for death (half an onion and froth of a beer…). The papyrus was purchased by the Chief of Egyptology (Georg Ebers) at the University of Leipzig in Germany where it currently resides. The story goes that the papyrus was discovered between the legs of a mummy. Adapted from http://spheresoflight.com.au/axismundi/content/images/ebers-papyrus-colonnes1-2.jpg.

Figure 3. Galega officinalis

This plant, also known as goat’s rue, French lilac, or Italian fitch, was used for many years to treat the symptoms of diabetes. In 1920, the anti-diabetic class of drugs called biguanides, originating from this plant, was introduced for the treatment of diabetes. Adapted from http://www.naturalmedicinefacts.info/plant/galega-officinalis.html.

Figure 4. Professor Jean Sterne at the Hospital Laennec, Paris, France

Introduction of metformin (“glucophage”) into clinical medicine. Reproduced with permission from Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes International. 2004;21(3):115-117.

Figure 5. Results of the meta-analyses comparing the efficacy of treatment with metformin vs. insulin in women with gestational diabetes

a. The panels present the beneficial effects of metformin vs. insulin in women with gestational diabetes that indicate a reduction in: 1) maternal weight gain during pregnancy; 2) gestational hypertension. Reproduced with permission from Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2013 May 27; 8:e64585. b. The panels present the beneficial effects of metformin vs. insulin in women with gestational diabetes that indicate a reduction in: 1) neonatal hypoglycemia; 2) large-for-gestational-age neonates; and 3) admissions to the neonatal intensive care unit.Reproduced with permission from Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med. 2017; 34:27-36. (Abbreviations: CI, confidence interval; IV, inverse variance; M-H, Mantel-Haenszel).

Figure 6. Effect of metformin on soluble fms-like tyrosine kinase-1 (sFlt1)/soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) secretion, soluble endoglin, and isoforms e15a and i13 expression in endothelial cells and placental tissue

Metformin reduced in a dose-dependent manner sFlt1 from (A) endothelial cells, (B) villous cytotrophoblast cells, and (C) preterm preeclamptic placental villous explants. Metformin also reduced endothelial cell expression of (D) the sFlt-1 i13 isoform, (E) villous cytotrophoblast cells, and (F) preterm preeclamptic placental villous explant messenger RNA expression of sFlt-1 e15a. Metformin reduced soluble endoglin secretion from (G) endothelial cells and (H) villous cytotrophoblast cells, but it did not change soluble endoglin secretion from (I) preterm preeclamptic placental villous explants. (The single asterisk indicates P <0.05; the double asterisk indicates P <0.01; the triple asterisk indicates P <0.0001; and the quadruple asterisk indicates P <0.00001). (Abbreviations: mM, millimolar; sENG, soluble endoglin; sFlt-1, Soluble fms-like tyrosine kinase-1). Modified with permission from Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, 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; 214:356.e1-356.e15.

Figure 7. Effect of soluble fms-like tyrosine kinase-1 (sFlt1)/soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and metformin on angiogenesis

Omental vessel rings cultured with sFlt1/sVEGFR-1 reduced the vessel outgrowth (white arrow, middle panel). This effect was resolved when metformin (1 mmol/L) was added to the culture media (right panel). (Abbreviations: sFlt-1, Soluble fms-like tyrosine kinase-1) Reproduced with permission from Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, 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; 214:356.e1-356.e15.

Figure 8. Effect of metformin on the mitochondrial respiratory transport chain complex 1

Metformin crosses the plasma membrane of the cell by passive diffusion, and the mitochondria is its main intracellular target. Metformin inhibits mitochondrial respiratory transport chain complex 1 and induces a decrease in the reduced form of nicotinamide adenosine dinucleotide (NADH) oxidation, proton pumping across the inner mitochondrial membrane, and the oxygen consumption rate, leading to a reduction of adenosine triphosphate (ATP) synthesis. (Abbreviations: ADP, Adenosine pyrophosphate; ATP, Adenosine triphosphate; Cyt c, cytochrome complex; FAD, flavin adenine dinucleotide; H+, hydrogen ion; H2O, water; NAD, Nicotinamide Adenine Dinucleotide; OCT, organic cation transporter) Reproduced with permission from Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012; 122:253-70.

Figure 9. Nutrient-sensing pathways in the evolution of species from unicellular to multicellular organisms

Unicellular organisms have two distinct nutrient pathways (PII and chemoreceptors), while fungi evolved three distinct nutrient-sensing pathways (SPS, Snf3/Rgt2, and MEP2). are denoted, followed by the sensing pathways that are conserved from yeast to man. Blue bars indicate the presence of the nutrient-sensing pathways used by different organisms. (Abbreviations: AMPK, 5′ adenosine monophosphate-activated protein kinase; GCN2, general control nonderepressible 2; MEP, 2-C-methyl-D-erythritol 4-phosphate; SPS, Ssy1-Ptr3-Ssy5; TOR, target of rapamycin) Reproduced with permission from Chantranupong L, Wolfson RL, Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell. 2015; 161:67-83.

Figure 10. Mechanisms of nutrient-sensing within unicellular and multicellular organisms

Panel A: Prokaryotes can sense amino acids through a variety of sensors present in the cytosol and extracellular compartments. Panel B: Similarly, yeast cells sense extracellular amino acids via plasma membrane transporters and cytosolic sensors. Eukaryote cells have another potential compartment, such as a vacuole, where sensing may occur. Panel C: In mammalian cells, sensing may occur via cell membrane transporters in the cytosol and within the lysosome. (Abbreviations: mTORC1, mechanistic target of rapamycin complex 1;) Reproduced with permission from Chantranupong L, Wolfson RL, Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell. 2015; 161:67-83.

Figure 11. Effect of maternal nutrition on the placental nutritional sensing system and fetal growth

The placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring. Maternal under-nutrition decreases circulating levels of IGF-I, leptin, and insulin and increases maternal serum adiponectin concentrations, leading to low fetal nutrient availability. Maternal over-nutrition is associated with increased insulin, Insulin-like growth factor-1 (IGF-1), and leptin concentrations in the maternal circulation and decreased levels of circulating levels of adiponectin, leading to fetal overgrowth. The placenta integrates maternal and fetal nutritional signals with information from intrinsic nutrient sensors such as mammalian target of rapamycin (mTOR) signaling. (Abbreviations: IGF-1, Insulin-like growth factor-1; mTOR, mechanistic target of rapamycin) Modified with permission from Jansson T, Powell TL. Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol. 2013; 56:591-601; and Jansson T, Aye IL, Goberdhan DC. The emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta. 2012; 33 Suppl 2: e23-e29 and https://clipartfest.com/download/2ccb316331956e87398d72be2d6d14e49c1a9be8.html

Figure 12. Metformin suppresses cell growth and promotes longevity

Metformin slows Caenorhabditis elegans (roundworm) growth by inhibiting the mitochondrial electron transport chain, which limits the transit of the RagC protein through the nuclear pore complex resulting in a reduced activity of the mechanistic target of rapamycin complex 1 (mTORC1). The metformin-induced inhibition of mTORC1 leads to the upregulation of the transcription factor Skn-1/Nrf-2 (a regulator of antioxidant genes) and the expression of acyl-CoA dehydrogenase family member-10 (ACAD10) gene. (Abbreviations: ACAD10, acyl-CoA dehydrogenase family member-10; mTORC1, mechanistic target of rapamycin complex 1; NPC, nuclear pore complex; RagC, Ras-related GTP binding C; RNAi, RNA interference; Skn-1/Nrf-2, protein skinhead-1/nuclear-factor-erythroid-related factor-2). Reproduced with permission from Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, Soukas AA. An ancient, unified mechanism for metformin growth inhibition in C. elegans and cancer. Cell. 2016; 167:1705-1718.e13.