Review Articles

The Relationship Between Folate, Vitamin B12 and Gestational Diabetes Mellitus With Proposed Mechanisms and Foetal Implications

Abstract

The incidence of gestational diabetes mellitus (GDM) is rising, which warrants attention due to the associated complications during pregnancy and in the long term for both mother and offspring. Studies have suggested a relationship between maternal folate (vitamin B9) and vitamin B12 status and GDM risk. Seemingly the most problematic scenario occurs when there is B-vitamin imbalance, with high folate and low vitamin B12. This nutritional state can occur in vitamin B12 deficient women who exceed the recommended folic acid supplementation. However, the pathological mechanisms behind this relationship are currently unclear and are explored in this review article. A high folate/low B12 can lead to a functional folate deficiency through the methyl-trap phenomenon, impairing re-methylation of homocysteine and regeneration of folates for DNA synthesis and repair. Consequently elevated homocysteine concentration leads to endothelial dysfunction and oxidative stress. Vitamin B12 deficiency also leads to an impairment of the conversion of methylmalonyl-CoA to succinyl-CoA, which has been associated with insulin resistance. Insulin resistance is thought to contribute to the etiology of GDM. More studies are needed to confirm the impact of these and other mechanisms on disease development. However, it highlights a potential avenue for GDM risk modification through a vitamin B12 supplement and improvement of maternal metabolic health.

Li S, Hou Y, Yan X, Wang Y, Shi C, Wu X, et al. Joint effects of folate and vitamin B12 imbalance with maternal characteristics on gestational diabetes mellitus. J Diabetes 2019; 11: 744-51.

Lai JS, Pang WW, Cai S, Lee YS, Chan JKY, Shek LPC, et al. High folate and low vitamin B12 status during pregnancy is associated with gestational diabetes mellitus. Clin Nutr 2018; 37: 940-7.

Krishnaveni GV, Hill JC, Veena SR, Bhat DS, Wills AK, Karat CL, et al. Low plasma vitamin B12 in pregnancy is associated with gestational 'diabesity' and later diabetes. Diabetologia 2009; 52: 2350-8.

Lavery JA, Friedman AM, Keyes KM, Wright JD, Ananth CV. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG 2017; 124: 804-13.

Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes Care

; 31: 899-904.

HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991-2002.

Appling DR. Compartmentation of folate-mediated one-carbon metabolism in eukaryotes. FASEB J 1991; 5: 2645-51.

Sobczynska-Malefora A, Harrington DJ. Laboratory assessment of folate (vitamin B9) status. J Clin Pathol 2018; 71: 949-56.

Scott J, Weir D. Folate/vitamin B12 inter-relationships. Essays Biochem 1994; 28: 63-72.

Sobczynska-Malefora A, Gorska R, Pelisser M, Ruwona P, Witchlow B, Harrington DJ. An audit of holotranscobalamin ("Active" B12) and methylmalonic acid assays for the assessment of vitamin B12 status: application in a mixed patient population. Clin Biochem 2014; 47: 82-6.

Dalmia A, Dib MJ, Maude H, Harrington DJ, Sobczynska-Malefora A, Andrew T, et al. A genetic epidemiological study in British adults and older adults shows a high heritability of the combined indicator of vitamin B12 status (cB12) and connects B12 status with utilization of mitochondrial substrates and energy metabolism. J Nutr Biochem 2019; 70: 156-63.

Hoffbrand AV, Jackson BF. Correction of the DNA synthesis defect in vitamin B12 deficiency by tetrahydrofolate: evidence in favour of the methyl-folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency. Br J Haematol 1993; 83: 643-7.

Green R, Allen LH, Bjorke-Monsen AL, Brito A, Gueant JL, Miller JW, et al. Vitamin B12 deficiency. Nat Rev Dis Primers 2017; 3: 17040.

Sobczynska-Malefora A, Ramachandran R, Cregeen D, Green E, Bennett P, Harrington DJ, et al. An infant and mother with severe B12 deficiency: vitamin B12 status assessment should be determined in pregnant women with anaemia. Eur J Clin Nutr 2017; 71: 1013-5.

Czeizel AE, Dudas I, Vereczkey A, Banhidy F. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Nutrients 2013; 5: 4760-75.

Safi J, Joyeux L, Chalouhi GE. Periconceptional folate deficiency and implications in neural tube defects.

J Pregnancy 2012; 2012: 295083.

van Gool JD, Hirche H, Lax H, De Schaepdrijver L. Folic acid and primary prevention of neural tube defects:

A review. Reprod Toxicol 2018; 80: 73-84.

DigitalNHS. 2015 National Pregnancy in Diabetes (NPID) audit report. 2016.

Allen LH. How common is vitamin B-12 deficiency?

Am J Clin Nutr 2009; 89: 693S-6S.

Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D. How prevalent is vitamin B(12) deficiency among vegetarians? Nutr Rev 2013; 71: 110-7.

Sukumar N, Venkataraman H, Wilson S, Goljan I, Selvamoni S, Patel V, et al. Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes. Nutrients 2016; 8: 768.

Morkbak AL, Hvas AM, Milman N, Nexo E. Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregnancy and postpartum. Haematologica 2007; 92: 1711-2.

Varela-Moreiras G, Murphy MM, Scott JM. Cobalamin, folic acid, and homocysteine. Nutr Rev 2009; 67 Suppl 1:S69-72.

Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet 2001; 358: 2069-73.

Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes care 2007; 30 Suppl 2:S112-9.

Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract 2014; 103: 176-85.

Buckley BS, Harreiter J, Damm P, Corcoy R, Chico A, Simmons D, et al. Gestational diabetes mellitus in Europe: prevalence, current screening practice and barriers to screening. A review. Diabet Med 2012; 29: 844-54.

Idzior-Walus B, Cyganek K, Sztefko K, Seghieri G, Breschi MC, Walus-Miarka M, et al. Total plasma homocysteine correlates in women with gestational diabetes. Arch Gynecol Obstet 2008; 278: 309-13.

Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 2008; 51: 29-38.

Zhu B, Ge X, Huang K, Mao L, Yan S, Xu Y, et al. Folic Acid Supplement Intake in Early Pregnancy Increases Risk of Gestational Diabetes Mellitus: Evidence From a Prospective Cohort Study. Diabetes Care 2016; 39: e36-7.

Cigerli O, Parildar H, Dogruk Unal A, Tarcin O, Kut A, Eroglu H, et al. Vitamin Deficiency and Insulin Resistance in Nondiabetic Obese Patients. Acta Endocrinol (Buchar) 2016; 12: 319-27.

Ho M, Halim JH, Gow ML, El-Haddad N, Marzulli T, Baur LA, et al. Vitamin B12 in obese adolescents with clinical features of insulin resistance. Nutrients 2014; 6: 5611-8.

Narang M, Singh M, Dange S. Serum Homocysteine, Vitamin B12 and Folic Acid Levels in Patients with Metabolic Syndrome. J Assoc Physicians India 2016; 64: 22-6.

Guven A, Inanc F, Kilinc M, Ekerbicer H. Plasma homocysteine and lipoprotein (a) levels in Turkish patients with metabolic syndrome. Heart Vessels 2005; 20: 290-5.

Adaikalakoteswari A, Jayashri R, Sukumar N, Venkataraman H, Pradeepa R, Gokulakrishnan K, et al. Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes. Cardiovasc Diabetol 2014; 13: 129.

Satapathy S, Bandyopadhyay D, Patro BK, Khan S, Naik S. Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: A multi-arm randomized controlled clinical trial. Complement Ther Med 2020; 53: 102526.

Crovetto F, Lattuada D, Rossi G, Mangano S, Somigliana E, Bolis G, et al. A role for mitochondria in gestational diabetes mellitus? Gynecol Endocrinol 2013; 29: 259-62.

Zheng LD, Linarelli LE, Liu L, Wall SS, Greenawald MH, Seidel RW, et al. Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans. Clin Epigenetics 2015; 7: 60.

Jarrett JT, Hoover DM, Ludwig ML, Matthews RG. The mechanism of adenosylmethionine-dependent activation of methionine synthase: a rapid kinetic analysis of intermediates in reductive methylation of Cob(II)alamin enzyme. Biochemistry 1998; 37: 12649-58.

Tam C, O'Connor D, Koren G. Circulating unmetabolized folic Acid: relationship to folate status and effect of supplementation. Obstet Gynecol Int 2012; 2012: 485179.

Plumptre L, Masih SP, Ly A, Aufreiter S, Sohn KJ, Croxford R, et al. High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. Am J Clin Nutr 2015; 102: 848-57.

Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006; 136: 189-94.

Zhao YH, Wang DP, Zhang LL, Zhang F, Wang DM, Zhang WY. Genomic expression profiles of blood and placenta reveal significant immune-related pathways and categories in Chinese women with gestational diabetes mellitus. Diabet Med 2011; 28: 237-46.

Chiba H, Fukui A, Fuchinoue K, Funamizu A, Tanaka K, Mizunuma H. Expression of Natural Cytotoxicity Receptors on and Intracellular Cytokine Production by NK Cells in Women with Gestational Diabetes Mellitus. Am J

Reprod Immunol 2016; 75: 529-38.

Swaroop JJ, Rajarajeswari D, Naidu JN. Association of TNF-alpha with insulin resistance in type 2 diabetes mellitus. Indian J Med Res 2012; 135: 127-30.

Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 2000; 71: 885-92.

Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A 2007; 104: 19351-6.

Mahajan A, Sapehia D, Thakur S, Mohanraj PS, Bagga R, Kaur J. Effect of imbalance in folate and vitamin B12 in maternal/parental diet on global methylation and regulatory miRNAs. Sci Rep 2019; 9: 17602.

Davegardh C, Garcia-Calzon S, Bacos K, Ling C. DNA methylation in the pathogenesis of type 2 diabetes in humans. Mol Metab 2018; 14: 12-25.

Selhub J. Public health significance of elevated homocysteine. Food Nutr Bull 2008; 29: S116-25.

Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J 2015; 14: 6.

Huang T, Ren J, Huang J, Li D. Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach. BMC Genomics 2013; 14: 867.

Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, Rifai N, et al. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care 2001; 24: 1403-10.

Guven MA, Kilinc M, Batukan C, Ekerbicer HC, Aksu T. Elevated second trimester serum homocysteine levels in women with gestational diabetes mellitus. Arch Gynecol Obstet 2006; 274: 333-7.

Seghieri G, Breschi MC, Anichini R, De Bellis A, Alviggi L, Maida I, et al. Serum homocysteine levels are increased in women with gestational diabetes mellitus. Metabolism 2003; 52: 720-3.

Deng M, Zhou J, Tang Z, Xiang J, Yi J, Peng Y, et al. The correlation between plasma total homocysteine level and gestational diabetes mellitus in a Chinese Han population. Sci Rep 2020; 10: 18679.

Radzicka S, Ziolkowska K, Zaborowski MP, Brazert J, Pietryga M. Serum homocysteine and vitamin B12 levels in women with gestational diabetes mellitus. Ginekol Pol 2019; 90: 381-7.

Yan Y, Wu X, Wang P, Zhang S, Sun L, Zhao Y, et al. Homocysteine promotes hepatic steatosis by activating the adipocyte lipolysis in a HIF1alpha-ERO1alpha-dependent

oxidative stress manner. Redox Biol 2020; 37: 101742.

Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis 2017; 16: 203.

Bar-On H, Kidron M, Friedlander Y, Ben-Yehuda A, Selhub J, Rosenberg IH, et al. Plasma total homocysteine levels in subjects with hyperinsulinemia. Journal of internal medicine 2000; 247: 287-94.

Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 55: 1028-35.

Bjorke Monsen AL, Ueland PM. Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence. Am J Clin Nutr 2003; 78: 7-21.

Katre P, Bhat D, Lubree H, Otiv S, Joshi S, Joglekar C, et al. Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12 and high folate status. Asia Pac J Clin Nutr 2010; 19: 335-43.

Cho NH, Lim S, Jang HC, Park HK, Metzger BE. Elevated homocysteine as a risk factor for the development of diabetes in women with a previous history of gestational diabetes mellitus: a 4-year prospective study. Diabetes Care 2005; 28: 2750-5.

Finer S, Saravanan P, Hitman G, Yajnik C. The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. Diabet Med 2014; 31: 263-72.

Sukumar N, Adaikalakoteswari A, Venkataraman H, Maheswaran H, Saravanan P. Vitamin B12 status in women of childbearing age in the UK and its relationship with national nutrient intake guidelines: results from two National Diet and Nutrition Surveys. BMJ Open 2016; 6: e011247.

Adaikalakoteswari A, Vatish M, Alam MT, Ott S, Kumar S, Saravanan P. Low Vitamin B12 in Pregnancy Is Associated With Adipose-Derived Circulating miRs Targeting PPARgamma and Insulin Resistance. J Clin Endocrinol Metab 2017; 102: 4200-9.

Ahmad S, Kumar KA, Basak T, Bhardwaj G, Yadav DK, Lalitha A, et al. PPAR signaling pathway is a key modulator of liver proteome in pups born to vitamin B(12) deficient rats. J Proteomics 2013; 91: 297-308.

Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH. Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia 2014; 57: 110-21.

Krishnaveni GV, Veena SR, Johnson M, Kumaran K, Jones A, Bhat DS, et al. Maternal B12, Folate and Homocysteine Concentrations and Offspring Cortisol and Cardiovascular Responses to Stress. J Clin Endocrinol Metab 2020; 105: e2591-9.

Yajnik CS. Nutrient-mediated teratogenesis and fuel-mediated teratogenesis: two pathways of intrauterine programming of diabetes. Int J Gynaecol Obstet 2009; 104 Suppl 1:S27-31.

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IssueVol 15, No 3 (September 2021) QRcode
SectionReview Articles
DOI https://doi.org/10.18502/jfrh.v15i3.7131
Keywords
Pregnancy Gestational Diabetes Vitamin B 12 Folic Acid Insulin Resistance

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1.
Maher A, Sobczyńska-Malefora A. The Relationship Between Folate, Vitamin B12 and Gestational Diabetes Mellitus With Proposed Mechanisms and Foetal Implications. J Family Reprod Health. 2021;15(3):141-149.