Calcium-Deficiency during Pregnancy Affects Insulin Resistance in Offspring

Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.

Severe malnutrition or famine exposure in childhood and cardiometabolic non-communicable disease later in life: a systematic review

IntroductionChild malnutrition (undernutrition) and adult non-communicable diseases (NCDs) are major global public health problems. While convincing evidence links prenatal malnutrition with increased risk of NCDs, less is known about the long-term sequelae of malnutrition in childhood. We therefore examined evidence of associations between postnatal malnutrition, encompassing documented severe childhood malnutrition in low/middle-income countries (LMICs) or famine exposure, and later-life cardiometabolic NCDs.MethodsOur peer-reviewed search strategy focused on ‘severe childhood malnutrition’, ‘LMICs’, ‘famine’, and ‘cardiometabolic NCDs’ to identify studies in Medline, Embase, Global Health, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. We synthesised results narratively and assessed study quality with the UK National Institute for Health and Care Excellence checklist.ResultsWe identified 57 studies of cardiometabolic NCD outcomes in survivors of documented severe childhood malnutrition in LMICs (n=14) and historical famines (n=43). Exposure to severe malnutrition or famine in childhood was consistently associated with increased risk of cardiovascular disease (7/8 studies), hypertension (8/11), impaired glucose metabolism (15/24) and metabolic syndrome (6/6) in later life. Evidence for effects on lipid metabolism (6/11 null, 5/11 mixed findings), obesity (3/13 null, 5/13 increased risk, 5/13 decreased risk) and other outcomes was less consistent. Sex-specific differences were observed in some cohorts, with women consistently at higher risk of glucose metabolism disorders and metabolic syndrome.ConclusionSevere malnutrition or famine during childhood is associated with increased risk of cardiometabolic NCDs, suggesting that developmental plasticity extends beyond prenatal life. Severe malnutrition in childhood thus has serious implications not only for acute morbidity and mortality but also for survivors’ long-term health. Heterogeneity across studies, confounding by prenatal malnutrition, and age effects in famine studies preclude firm conclusions on causality. Research to improve understanding of mechanisms linking postnatal malnutrition and NCDs is needed to inform policy and programming to improve the lifelong health of severe malnutrition survivors.

Short-term and long-term distributional consequences of prenatal malnutrition and stress: using Ramadan as a natural experiment

IntroductionFetal environments play significant roles in determining adult well-being, particularly as they relate to non-communicable diseases and skill formation. We studied gender-specific distributional consequences of fetal environment (in the form of in-utero exposure to Ramadan, the Islamic holy month of fasting), in Indonesia, on birth weights, performance on Raven’s Colored Progressive Matrices (CPM), math scores, hours worked and earnings.MethodsWe used quantile regressions to conduct a quantitative comparison of distributional consequences, by gender, of full month exposures to Ramadan in-utero on outcomes of interest. Our data included Muslim children and adults measured during rounds 1 and 4 of the Indonesian Family Life Survey. Our main outcome measures were: birth weights—559 observations (females) and 624 (males); Raven’s CPM scores—1693 (females) and 1821 (males) for 8–15 year olds; math test scores—1696 (females) and 1825 (males) for 8–15 year olds; hours worked—3181 (females) and 4599 (males) for 18–65 year olds; earnings—2419 (females) and 4019 (males) for 18–65 year olds.ResultsFull month of exposure to Ramadan in-utero led to significant reductions at the 5% significance level that were concentrated in the bottom halves of the outcome distributions: among 8–15 years, lower scores on Raven’s CPM tests for females (mean: −9.2%, 10thQ: −19%, 25th Q: −19.4%) and males (mean: −5.6%, 10thQ: −12.5%); lower math scores for females (mean: −8.6%, 25thQ: −15.9%) and males (mean: −8.5%, 10thQ: −13.6%); among females 18–65 years, significant reduction in hours worked (mean: −7.5%, 10thQ: − 26.3%).ConclusionEvents during the fetal period have far-reaching consequences for females and males in the lowest (10th and 25th) quantiles of outcome distributions, affecting the ‘relatively poor’ the most. These results call for caution in interpreting studies on child development that rely on mean comparisons alone.

Prenatal Malnutrition-Induced Epigenetic Dysregulation as a Risk Factor for Type 2 Diabetes

Type 2 diabetes (T2D) is commonly regarded as a disease originating from lifestyle-related factors and typically occurring after the age of 40. There is, however, consistent experimental and epidemiological data evidencing that the risk for developing T2D may largely depend on conditions early in life. In particular, intrauterine growth restriction (IUGR) induced by poor or unbalanced nutrient intake can impair fetal growth and also cause fetal adipose tissue and pancreatic β-cell dysfunction. On account of these processes, persisting adaptive changes can occur in the glucose-insulin metabolism. These changes can include reduced ability for insulin secretion and insulin resistance, and they may result in an improved capacity to store fat, thereby predisposing to the development of T2D and obesity in adulthood. Accumulating research findings indicate that epigenetic regulation of gene expression plays a critical role in linking prenatal malnutrition to the risk of later-life metabolic disorders including T2D. In animal models of IUGR, changes in both DNA methylation and expression levels of key metabolic genes were repeatedly found which persisted until adulthood. The causal link between epigenetic disturbances during development and the risk for T2D was also confirmed in several human studies. In this review, the conceptual models and empirical data are summarized and discussed regarding the contribution of epigenetic mechanisms in developmental nutritional programming of T2D.

DNA methylation signatures link prenatal famine exposure to growth and metabolism

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.