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      Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children

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          Abstract

          Aims/hypothesis

          In an Indian birth cohort, higher maternal homocysteine concentration in pregnancy was associated with lower birthweight of the offspring. Lower maternal vitamin B12 and higher folate concentrations were associated with higher offspring insulin resistance. Disordered one-carbon metabolism during early development may increase later metabolic risk. We explored these associations in another birth cohort in India at three age points.

          Methods

          We measured plasma vitamin B12, folate and homocysteine concentrations at 30 ± 2 weeks’ gestation in 654 women who delivered at one hospital. Neonatal anthropometry was recorded, and the children’s glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age. Insulin resistance was estimated using HOMA of insulin resistance (HOMA-IR).

          Results

          Maternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements ( p < 0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p = 0.007) and 9.5 years of age (120 min; p = 0.02). Higher maternal folate concentrations were associated with higher HOMA-IR in the children at 9.5 ( p = 0.03) and 13.5 years of age ( p = 0.03). Maternal vitamin B12 concentrations were unrelated to offspring outcomes.

          Conclusions/interpretation

          Maternal vitamin B12 status did not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations with birth size, and with childhood insulin resistance and glycaemia in the offspring, suggest a role for nutritionally driven disturbances in one-carbon metabolism in fetal programming of diabetes.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-013-3086-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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          Most cited references32

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          DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.

          A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.
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            Fetal nutrition and cardiovascular disease in adult life.

            Babies who are small at birth or during infancy have increased rates of cardiovascular disease and non-insulin-dependent diabetes as adults. Some of these babies have low birthweights, some are small in relation to the size of their placentas, some are thin at birth, and some are short at birth and fail to gain weight in infancy. This paper shows how fetal undernutrition at different stages of gestation can be linked to these patterns of early growth. The fetuses' adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones. Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them, may link fetal undernutrition with abnormal structure, function, and disease in adult life.
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              Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth: Pune Maternal Nutrition Study.

              One third of the Indian babies are of low birth weight (<2.5 kg), and this is attributed to maternal undernutrition. We therefore examined the relationship between maternal nutrition and birth size in a prospective study of 797 rural Indian women, focusing on macronutrient intakes, dietary quality and micronutrient status. Maternal intakes (24-h recall and food frequency questionnaire) and erythrocyte folate, serum ferritin and vitamin C concentrations were measured at 18 +/- 2 and 28 +/- 2 wk gestation. Mothers were short (151.9 +/- 5.1 cm) and underweight (41.7 +/- 5.1 kg) and had low energy and protein intakes at 18 wk (7.4 +/- 2.1 MJ and 45.4 +/- 14.1 g) and 28 wk (7.0 +/- 2.0 MJ and 43.5 +/- 13.5 g) of gestation. Mean birth weight and length of term babies were also low (2665 +/- 358 g and 47.8 +/- 2.0 cm, respectively). Energy and protein intakes were not associated with birth size, but higher fat intake at wk 18 was associated with neonatal length (P < 0.001), birth weight (P < 0.05) and triceps skinfold thickness (P < 0.05) when adjusted for sex, parity and gestation. However, birth size was strongly associated with the consumption of milk at wk 18 (P < 0.05) and of green leafy vegetables (P < 0.001) and fruits (P < 0.01) at wk 28 of gestation even after adjustment for potentially confounding variables. Erythrocyte folate at 28 wk gestation was positively associated with birth weight (P < 0.001). The lack of association between size at birth and maternal energy and protein intake but strong associations with folate status and with intakes of foods rich in micronutrients suggest that micronutrients may be important limiting factors for fetal growth in this undernourished community.
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                Author and article information

                Contributors
                gv.krishnaveni@gmail.com
                Journal
                Diabetologia
                Diabetologia
                Diabetologia
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0012-186X
                1432-0428
                26 October 2013
                26 October 2013
                2014
                : 57
                : 110-121
                Affiliations
                [ ]Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, P.O. Box 38, Mandi Mohalla, Mysore 570021 India
                [ ]Diabetes Unit, KEM Hospital, Pune, India
                [ ]MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, UK
                Article
                3086
                10.1007/s00125-013-3086-7
                3855580
                24162586
                14d0d1ed-9e9b-4004-bc0b-d95cb1686808
                © The Author(s) 2013

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 30 June 2013
                : 30 September 2013
                Categories
                Article
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2014

                Endocrinology & Diabetes
                child,folate,homocysteine,insulin resistance,pregnancy,programming,vitamin b12
                Endocrinology & Diabetes
                child, folate, homocysteine, insulin resistance, pregnancy, programming, vitamin b12

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