medigraphic.com
Federación Mexicana de Ginecología y Obstetricia, A.C.

2020, Número 03

<< Anterior Siguiente >>

Ginecol Obstet Mex 2020; 88 (03)


Metformina: interacciones moleculares, celulares y su repercusión en la Obstetricia. Revisión bibliográfica

Ayala-Yáñez R, Martínez-Ruíz M, Alonso-de Mendieta M, Cassis-Bendeck DM, Frade-Flores R

Idioma: Español
Referencias bibliográficas: 58
Paginas: 161-175
Archivo PDF: 354.30 Kb.


RESUMEN

Objetivo: Identificar los mecanismos celulares más reconocidos de la metformina y su relación con patologías en Obstetricia y determinar las moléculas y vías involucradas con potencial terapéutico.
Metodología: Estudio retrospectivo efectuado con base en la búsqueda de artículos registrados en Pubmed y Cochrane publicados en inglés entre los años 2000 a 2019 que contuvieran las palabras clave (MeSH): “Metformin”; “Celular mechanisms”; “AMPK”; “LKB1”; “Gestational diabetes”, “Abortion” y “Preeclampsia”.
Resultados: Se encontraron 1750 artículos que contenían las palabras clave de búsqueda; al final solo se analizaron 57. En estos se concluye que la intervención con este fármaco inhibe el complejo I de la cadena respiratoria mitocondrial, con repercusión en varios procesos celulares. La diabetes gestacional, el aborto y la preeclampsia se consideraron por su incidencia y relevancia obstétrica, y por la indicación de la metformina en su tratamiento. Se identificaron los mecanismos involucrados en el efecto colateral gastrointestinal y la asociación con los mecanismos celulares influidos por la metformina. En los padecimientos obstétricos se identificaron los procesos metabólicos para tratamiento común, la diabetes gestacional fue la más identificada por la experiencia en diabetes mellitus.
Conclusiones: Si bien la metformina tiene una indicación clara en pacientes con diabetes gestacional, los resultados son insuficientes para aborto; en preeclampsia los mecanismos intervenidos pueden tener mayor potencial terapéutico y preventivo.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60:1566-76. https://doi.org/10.1007/s00125-017- 4318-z.

  2. Hesse G, Taubmann G. Die Wirkung des Biguanids und seiner Derivate auf den Zuckerstoffwechsel. Arch Exp Path Pharmacol 1929;142:290-308 (trad. Aleman).

  3. Pasik C. Diabetes and the biguanides: the mystery of each. Glucophage: serving diabetology for 40 years. Groupe Lipha, Lyon, 1997: 79.

  4. World Health Organization (2015). WHO model list of essential medicines. www.who.int/medicines/publications/ essentialmedicines/EML_2015_FINAL_amended_ NOV2015.pdf?ua=1.

  5. Maida A, et al. Metformin regulates de incretin receptor axis via la pathway dependent on peroxisome proliferatoractivated receptor-alpha in mice. Diabetologia 2011; 54:339-49. https://doi.org/10.1007/s00125-010-1937-z.

  6. Shu Y, et al. Effect of genetic variation in the organic cation transporter 1 (OCT-1) on metformin action. J Clin Invest 2007; 117: 1422-31. doi: 10.1172/JCI30558.

  7. Yang P, et al. Efectividad de la metformina en pacientes con diabetes tipo II según variantes del gen SLC22A1. Acta Bioquím Clín Latinoam 2014; 48 (2): 229-35.

  8. Zhou G, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167- 74. doi: 10.1172/JCI13505.

  9. Xiao B, et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011; 472:2 30-33. https://doi. org/10.1038/nature09932.

  10. Viollet B, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012;122:253-270. https://doi.org/10.1042/CS20110386.

  11. Stephenne X, et al Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011; 54: 3101-110. https://doi.org/10.1007/s00125-011-2311-5.

  12. McInnes KJ, et al. Regulation of LKB1 expression by sex hormones in adipocytes. Int J Obes. 2011;36:982-5. https:// doi.org/10.1038/ijo.2011.172.

  13. Shaw RJ, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 1642-6. doi: 10.1126/science.1120781.

  14. He L, et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137: 635-46. doi: 10.1016/j. cell.2009.03.016.

  15. Kim YD, et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 2008; 57:306-14.doi: 10.2337/db07-0381.

  16. Takashima M, et al. Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action. Diabetes 2010; 59:1608-15. doi: 10.2337/db09-1679.

  17. Foretz M, et al. Metformin inhibits hepatic gluconeogenesis in mice independently for the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120: 2355-69. doi:10.1172/JCI40671.

  18. Zang M, et al. AMP activated protein kinase is required for the lipid lowering effect of metformin in insulin resistant human HepG2 cells. J Biol Chem 2004; 279: 47898-905. doi: 10.1074/jbc.M408149200.

  19. Dujic T, et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a Go DARTS study. Diabetes 2015; 64: 1786-93. doi: 10.2337/ db14-1388.

  20. Zhou K, et al. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2014;2:481-87. https://doi. org/10.1016/S2213-8587(14)70050-6.

  21. Graham GG, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81-98. doi: 10.2165/11534750-000000000-00000.

  22. Han TK, et al. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers. J Pharmacol Exp Ther. 2015; 352:519-28. doi: 10.1124/jpet.114.220350.

  23. Cubeddu LX, et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 85-91. https://doi.org/10.1007/s002109900152.

  24. McCreight LJ, et al. Metformin and the gastrointestinal tract. Diabetología 2016; 59:426-35. doi: 10.1007/s00125- 015-3844-9.

  25. Bailey CJ, et al. Metformin and the intestine. Diabetologia 2008; 51: 1552-53. https://doi.org/10.1007/s00125- 008-1053-5.

  26. Mannucci E, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese non-diabetic subjects. Diabetes Care. 2001;24:489–494. doi: 10.2337/ diacare.24.3.489.

  27. Shin NR, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727- 35. doi: 10.1136/gutjnl-2012-303839.

  28. Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80:35– 5943. DOI: 10.1128/AEM.01357-14.

  29. Dirar AM, Doupis J. Gestational diabetes from A to Z. World J Diabetes 2017;8:489-506. DOI: 10.4239/wjd.v8.i12.489.

  30. Dainelli L, et al. Screening and management of gestational diabetes in Mexico: Results from a survey of multilocation, multi-health care institution practitioners. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2018;11:105-116. https://doi.org/10.2147/ DMSO.S160658.

  31. Diagnóstico y tratamiento de la diabetes en el embarazo. Guía de Práctica Clínica, México: Secretaría de Salud 03/11/2016. http://www.cenetec.salud.gob.mx/descargas/ gpc/CatalogoMaestro/320_IMSS_10_Diabetes_embarazo/ EyR_IMSS_320_10.pdf.

  32. Glueck CJ, et al. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: Prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 2004; 19:510-21. https://doi.org/10.1093/ humrep/deh109.

  33. Wu Y, et al. AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia 2012; 55: 245-54. https://doi.org/10.1007/s00125-011-2326-y.

  34. Lee H-Y, et al. Lack of metformin effect on mouse embryo AMPK activity: Implications for metformin treatment during pregnancy Diabetes Metab Res Rev 2014;30:23-30. https://doi.org/10.1002/dmrr.2451.

  35. Jastrow N, et al. Effect of birth weight on adverse obstetric outcomes in vaginal birth after cesarean delivery. Obstet Gynecol 2010; 115: 338-43. doi:10.1097/ AOG.0b013e3181c915da.

  36. Shah BR, et al. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diab Care 2008;31:1668-9. doi: 10.2337/dc08-0706

  37. Guerrero-Romero F, et al. Birthweight, family history of diabetes, and metabolic syndrome in children and adolescents. J of Pediatric 2010; 156:719-23. https://doi. org/10.1016/j.jpeds.2009.11.043.

  38. Chiswick C, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women. EMPOWaR: A randomized, double blind, placebo controlled trial. Lancet Diabetes Endocrinol 2015; 3: 778-86. https://doi. org/10.1016/S2213-8587(15)00219-3.

  39. Stanford FC, et al. Metformin vs Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med 2016; 374: 434-43. doi: 10.1056/NEJMoa1509819.

  40. Hyer S, Balani J, Shehata H. Metformin in Pregnancy: Mechanisms and Clinical Applications. Int J Mol Sci. 2018;19:1954.https://doi.org/10.3390/ijms19071954.

  41. Alqudah A, et al. Risk of preeclampsia in women taking metformin: A systematic review and meta-analysis. Diabet Med 2018;35:160-72. https://doi.org/10.1111/dme.13523.

  42. Rowan JA, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15. doi: 10.1056/NEJMoa0707193.

  43. Butalia S, et al. 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. https://doi.org/10.1111/dme.13150.

  44. Hyer S, et al. Metformin in Pregnancy: Mechanisms and clinical applications. Int J Mol Sci. 2018;19:1954. https:// doi.org/10.3390/ijms19071954.

  45. Simmons D. Safety considerations with pharmacological treatment of gestational diabetes mellitus. Drug Safety 2015;38:65-78. https://doi.org/10.1007/s40264-014- 0253-9.

  46. Rowan JA, et al. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes Res. Care 2018; 6: e000456. DOI: 10.1136/bmjdrc- 2017-000456.

  47. Brown J, et al. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review). Cochrane Database Syst Rev 2017; 1: CD011967. https://doi.org/10.1002/14651858.CD011967.pub2.

  48. Martis R, et al. Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews. Cochrane Database Syst Rev. 2018;8:CD012327. https://doi.org/10.1002/14651858.CD012327.pub2.

  49. Glueck CJ, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75:46-52. https://doi.org/10.1016/ S0015-0282(00)01666-6.

  50. Schermeck S, et al. Pregnancy outcome after first-trimester exposure to metformin: a prospective cohort study. Reprod Toxicol 2018; 81: 79-83. https://doi.org/10.1016/j. reprotox.2018.07.004.

  51. Osungbade KO, Ige OK. Public health perspectives of preeclampsia in developing countries: implication for health system strengthening. J Pregnancy 2011; PMC3087154. https://doi.org/10.1155/2011/481095.

  52. Abalos E, et al. Global and regional estimates of preeclampsia and eclampsia: a systematic review. European Journal of Obstetrics & Gynecology and Reproductive Biology 2013; 170: 1-7. https://doi.org/10.1016/j.ejogrb.2013.05.005.

  53. Brownfoot FC, et al. Metformin as a prevention and treatment for preeclampsia: Effects on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion, and endothelial dysfunction Am J Obstet Gynecol 2016; 214: 356e1-356.e15. https://doi.org/10.1016/j. ajog.2015.12.019.

  54. Cluver C, et al. A doble blind, randomised, placebo controlled trial to evaluate the efficacy of metformin to treat preterm preeclampsia (P12 Trial): study protocol. BMJ Open. 2019:9:e025809. 10.1136/bmjopen- 2018-025809.

  55. D’Ambrosio V, et al. Metformin reduces maternal weight gain in obese pregnant women: a systematic review and meta-analysis of two randomized controlled trials. Diabetes Metab Res Rev. 2019. https://doi.org/10.1002/ dmrr.3164.

  56. Nascimento IBD, et al. Evaluation of preeclampsia results after use of metformin in gestation: systematic review and meta-analysis. Rev Bras Ginecol Obstet 2018;40:713-21. DOI: 10.1055/s-0038-1675214.

  57. Pushpakom S, et al Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18: 41-

  58. https://doi.org/10.1038/nrd.2018.168.




2020     |     www.medigraphic.com