Role of maternal vitamin B12 on the metabolic health of the offspring: a contributor to the diabetes epidemic?

Abstract

There is increasing evidence, in humans and other mammals, that periconceptional nutritional status influences health in adulthood. This is called ‘foetal programming’ and is likely to be mediated through DNA methylation. Micronutrients, especially B vitamins such as folic acid and vitamin B12 play crucial roles in providing methyl groups for such reactions. This is called epigenetic regulation and may provide some clues to the epidemic of type 2 diabetes and cardiovascular disease. Evidence from mandatory folic acid fortification studies suggests that in the presence of adequate folic acid, neural tube defects due to B12 deficiency have tripled. Such ‘imbalance of high folic acid and low vitamin B12’ in the elderly causes cognitive impairment. A longitudinal study of young women in India showed that children born to those with ‘high folic acid and low B12’ had higher adiposity and insulin resistance. In addition to increased levels of folic acid, B12 deficiency is increasing in countries with mandatory folic acid fortification. Studies on the prevalence of vitamin B12 deficiency during pregnancy and in women of childbearing age, plus the effects of B12 supplementation are therefore urgently needed. This article reviews the role of vitamin B12 during pregnancy on the offspring’s metabolic risk.

Keywords

cardiovascular risk diabetes epigenetics foetal programming folate intrauterine environment maternal vitamin B12 pregnancy

References

IDF Diabetes Atlas. Brussels: International Diabetes Federation, 2008.

Rocchini AP Childhood obesity and a diabetes epidemic. N Engl J Med 2002;346:854-5.

Miller J. , Rosenbloom A. , Silverstein J. Childhood obesity. J Clin Endocrinol Metab 2004;89:4211-18.

Hales CN , Barker DJ Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis . Diabetologia 1992;35:595-601.

Hattersley AT , Tooke JE The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999;353:1789-92.

Barker DJ The developmental origins of adult disease. J Am Coll Nutr 2004;23(suppl):588S-595S.

Yajnik CS , Yudkin JS The Y-Y paradox. Lancet 2004;363:163.

Yajnik CS

The insulin resistance epidemic in India: fetal origins, later lifestyle, or both?

Nutr Rev 2001;59(1 Pt 1):1-9.

Forouhi NG , Sattar N. , Tillin T. et al. Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK. Diabetologia 2006;49:2580-8.

10.

Gunarathne A. , Patel JV , Potluri R. et al. Increased 5-year mortality in the migrant South Asian stroke patients with diabetes mellitus in the United Kingdom: the West Birmingham Stroke Project. Int J Clin Pract 2008;62:197-201.

11.

Yajnik CS , Fall CH , Coyaji KJ et al. Neonatal anthropometry: the thin- fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord 2003;27:173-80.

12.

Yajnik CS , Lubree HG , Rege SS et al. Adiposity and hyperinsulinemia in Indians are present at birth . J Clin Endocrinol Metab 2002;87:5575-80.

13.

Yajnik CS , Deshpande SS , Jackson AA 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.

14.

Williamson CS Nutrition in pregnancy. Nutrition Bulletin 2006;31:28-59.

15.

Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997; 24(Suppl 18):S18.

16.

Rosenberg IH Metabolic programming of offspring by vitamin B12/ folate imbalance during pregnancy. Diabetologia 2008;51:6-7.

17.

Roje S. S-Adenosyl-L-methionine: beyond the universal methyl group donor. Phytochemistry 2006;67:1686-98.

18.

Wilson J. , Langman MJ Relation of sub-acute combined degeneration of the cord to vitamin B 12 deficiency . Nature 1966; 212:787-9.

19.

Lumley J. , Watson L. , Watson M. , Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001;(3):CD001056.

20.

Ray JG , Blom HJ Vitamin B12 insufficiency and the risk of fetal neural tube defects. QJM 2003;96:289-95.

21.

Ray JG , Wyatt PR , Thompson MD et al. Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population. Epidemiology 2007;18:362-6.

22.

Jones KM , Ramirez-Zea M. , Zuleta C. , Allen LH Prevalent vitamin B-12 deficiency in twelve-month-old Guatemalan infants is predicted by maternal B-12 deficiency and infant diet. J Nutr 2007;137:1307-13.

23.

Schulpis K. , Spiropoulos A. , Gavrili S. et al. Maternal-neonatal folate and vitamin B12 serum concentrations in Greeks and in Albanian immigrants. J Hum Nutr Diet 2004;17:443-8.

24.

Molloy AM , Kirke PN , Brody LC et al. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull 2008; 29(Suppl):S101-11.

25.

Bhate V. , Deshpande S. , Bhat D. et al. Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children. Food Nutr Bull 2008; 29:249-54.

26.

Black MM Effects of vitamin B12 and folate deficiency on brain development in children . Food Nutr Bull 2008;29(Suppl):S126-31.

27.

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998;316:894-8.

28.

Scott JM , Weir DG The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 1981;2:337-40.

29.

Wald DS , Law M. , Morris JK Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis . BMJ 2002;325:1202.

30.

Zhou J. , Austin RC Contributions of hyperhomocysteinemia to atherosclerosis: Causal relationship and potential mechanisms. Biofactors 2009;35:120-9.

31.

Bazzano LA , Reynolds K. , Holder KN , He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006;296:2720-6.

32.

Albert CM , Cook NR , Gaziano JM et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008;299:2027-36.

33.

Ruderman NB , Park H. , Kaushik VK et al. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol Scand 2003;178:435-42.

34.

Bhargava SK , Sachdev HS , Fall CH et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004;350:865-75.

35.

Selhub J. , Morris MS , Jacques PF In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A 2007;104:19995-20000.

36.

Barker DJ The fetal and infant origins of disease. Eur J Clin Invest 1995;25:457-63.

37.

McMillen IC , Robinson JS Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85:571-633.

38.

Sinclair KD , Singh R. Modelling the developmental origins of health and disease in the early embryo. Theriogenology 2007;67:43-53.

39.

Morgan HD , Santos F. , Green K. et al. Epigenetic reprogramming in mammals. Hum Mol Genet 2005;14(Spec No 1):R47-58.

40.

Waterland RA , Jirtle RL Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23):5293-300.

41.

Lillycrop KA , Phillips ES , Jackson AA et al. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005;135:1382-6.

42.

Sinclair KD , Allegrucci C. , Singh R. 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.

43.

Allen LH

How common is vitamin B-12 deficiency?

Am J Clin Nutr 2009;89:693S-96S.

44.

Green R.

Is it time for vitamin B-12 fortification? What are the questions?

Am J Clin Nutr 2009;89:712S-716S.

45.

Recommended levels of folic acid and vitamin B12 fortification . Proceedings of a technical consultation convened by the Food and Nutrition Program of the Pan American Health Organization, the March of Dimes, and the Centers for Disease Control and Prevention. January 23-24, 2003. Washington, DC, USA. Nutr Rev 2004; 62(6 Pt 2):S1-64.

46.

Carmel R. Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiological effects. Food Nutr Bull 2008;29(Suppl):S177-87.