Early life determinants and T2DM

The Developmental Origins of Health and Disease (DOHaD) hypothesis originally proposed by David Barker offers an alternative explanation for the aetiology of type 2 diabetes mellitus and other non-communicable diseases. It suggests that nutrition during critical stages of development permanently alter the structure and metabolism of the cells, tissues, organs and systems (‘Programming’). Disease results from a suboptimal function of a programmed system, especially when faced by a challenging environment (mismatch). This chapter outlines the development of the hypothesis and its potential for primary (primordial) prevention.

The developmental origins of health and disease

Figure 1: (Click to enlarge) Type 2 diabetes mellitus – the conventional dogma (genetic + lifestyle) and the alternative explanation (programming) for its aetiology
Figure 1: (Click to enlarge) Type 2 diabetes mellitus – the conventional dogma (genetic + lifestyle) and the alternative explanation (programming) for its aetiology
Current preventive strategies to reduce type 2 diabetes mellitus (T2DM) can be termed secondary rather than primary prevention. The most promising lead for primary prevention comes from David Barker’s programming hypothesis (Figure 1). He suggested that alterations in the nutritional supply during critical stages of intra-uterine development permanently alter the structure and function of the fetal systems (fetal programming) [1]. The fetus depends on the mother for its nutritional needs, and therefore any disturbance in the maternal nutritional status or its supply to the fetus will adversely impact fetal growth. When nutrition is limited, it is preferentially used for the growth of the fetal brain. This redistribution of nutrition is thought to be achieved by increased blood flow to cephalic [pre-ductal] system at the cost of caudal (post-ductal) and sub-diaphragmatic organs like lungs, heart, liver, pancreas, kidneys etc. These individuals are susceptible to a range of diseases when challenged with adverse lifestyle including sarcopenic adiposity, reduced beta cell mass, insulin resistance, reduced number of nephrons etc. (Figure 2).

Figure 2: (Click to enlarge) Programming hypothesis – different pathways by which fetal undernutrition influences risk of adult chronic non-communicable disease; inadequate maternal nutrition or disturbances in maternal ability to transport nutrients to the growing fetus leads to fetal undernutrition. The fetus adapts by altering the structure and metabolism of its organs and tissues; these adaptations result in permanent changes which ‘programme’ the development of risk factors for non-communicable diseases in later life (Courtesy: MRC LIfecourse Edpimeiology Unit, Southampton)
Figure 2: (Click to enlarge) Programming hypothesis – different pathways by which fetal undernutrition influences risk of adult chronic non-communicable disease; inadequate maternal nutrition or disturbances in maternal ability to transport nutrients to the growing fetus leads to fetal undernutrition. The fetus adapts by altering the structure and metabolism of its organs and tissues; these adaptations result in permanent changes which ‘programme’ the development of risk factors for non-communicable diseases in later life (Courtesy: MRC LIfecourse Edpimeiology Unit, Southampton)
Early work in this field showed that the prevalence of T2DM and impaired glucose tolerance was highest in adults who had the lowest birth weights[2] (Figure 3). The relationship with birth weight was continuous and graded, without any threshold. These findings have subsequently been replicated in several parts of Figure 3: (Click to enlarge) Birth weight and type 2 diabetes mellitus and impaired glucose tolerance in Hertfordshire men aged 60-70; as birth weight increases, the prevalence of T2DM and IGT decreases[2]
Figure 3: (Click to enlarge) Birth weight and type 2 diabetes mellitus and impaired glucose tolerance in Hertfordshire men aged 60-70; as birth weight increases, the prevalence of T2DM and IGT decreases[2]
the world including developing countries[3]. It was however apparent that birth weight was not the major issue, and in fact, both low and high birth weights were associated with later T2DM indicating a U shaped relationship[4]. Subsequently, postnatal growth has also been shown to be associated with risk of T2DM; individuals with the highest risk of T2DM are those who had low birth weight but high current body mass index (BMI)[5][6]. The fetal programming hypothesis expanded to include postnatal factors and is now referred to as the ‘developmental origins of health and disease’ hypothesis (DOHaD).

Birth weight is not an exposure per se but a marker of a multitude of exposures including maternal nutrition. Presumptive evidence is available from ‘nature’s experiments. The ‘Dutch Famine’ study showed that mothers exposed to famine during mid and late pregnancy had lower birth weight babies (~150-200 g lower) than those who were not exposed; however exposure in early pregnancy did not show any effect. Both 120-min glucose and insulin concentrations were higher in individuals exposed at any time in pregnancy and those exposed during late pregnancy had a higher risk of impaired glucose tolerance and diabetes compared to those unexposed (21% v 15%; p>0.05)[7]. A study in Pune, India first demonstrated a direct link between maternal micronutrient intake and birth size; women who ate green leafy vegetables more frequently during pregnancy had babies of higher birth weight irrespective of total energy and protein intake [8]. Low maternal B12 during pregnancy predicted higher homocysteine which was associated with greater risk of small for gestational age babies. Higher folate concentrations during pregnancy predicted higher adiposity in the children, and lower vitamin B12 during pregnancy was associated with higher insulin resistance in their children at 6-years of age[9]. In a study in Bangalore, low B12 and folate as well as an imbalance between B12 and folate predicted higher risk of small for gestational age babies[10]. In Nepal, offspring of mothers with B12 deficiency during pregnancy had higher insulin resistance at 6-8 years of age[11]. Folate and B12 are methyl donors in the 1-carbon metabolism pathway. Deficiency of B12 and/or folate may inhibits the regeneration of methionoine and causes an increase in homocysteine and its related metabolites. This suggests a role of 1-carbon metabolism in fetal programming.

Fetal over nutrition (due to maternal obesity and hyperglycaemia) may also programme the offspring for T2DM. Studies from different parts provide support that the association between high birth weight and T2DM may be linked through maternal diabetes[12]. These babies are born larger, and develop early obesity, central obesity, higher insulin resistance and impaired glucose tolerance and T2DM.

The DOHaD hypothesis is strongly supported by animal studies showing that maternal nutritional status can influence disease outcomes in the offspring. Obesity, hypertension and diabetes can be programmed by under- or over-nourishing the fetus, by changing the pregnant mother’s diet. Evidence in humans is largely limited to observational studies, using birth weight or extreme nutritional situations (e.g. famine) as exposures. Some recent studies have followed up children whose mothers took part in nutritional supplementation trials. Indian adolescents whose pregnant mothers were supplemented with energy and protein had lower insulin resistance and arterial stiffness[13], and Nepali children whose mothers were supplemented with multiple micronutrients had lower blood pressure[14]. However, supplementation of Gambian women with energy and protein had no effect on the children’s body composition or blood pressure[15].

Mechanisms of nutritional fetal programming (Human + Animal)

The possible mechanisms are still poorly understood. The inheritance of genes contributing to both low birth weight and insulin secretion-action, and obesity and GDM has been suggested. However, shared genetic determinants for birth weight and glucose tolerance are uncommon with a small effect size[16]. Also offspring born to diabetic mothers had higher rates of obesity and T2DM compared to the offspring born before the diagnosis of the mother’s diabetes[17]. These findings suggested that the intra-uterine environment had a bigger influence on offspring diabetes than genes. It is likely that an interaction between genetic and environmental factors influences not only fetal growth but also the development of T2DM. The fetus adapts to an insult by altering the structure and metabolism of its organs and tissues; these adaptations result in permanent changes which ‘programme’ the development of risk factors for non-communicable diseases in later life.

Recent research suggests these effects may act through ‘epigenetic’ mechanisms that alter expression of genes without altering the base sequence. The most likely mechanisms may be through methylation of DNA and acetylation of histones; both processes modify gene expression and could result in different phenotypes for the same genotype[18]. Animal studies have shown that epigenetic changes during early development may be an important mechanism linking early nutrition to later health. The normal process of de- and re-methylation of fetal DNA in early gestation is nutritionally sensitive. Nutritional interventions in pregnant mothers (mostly using methyl donors such as vitamin B12, folic acid, betaine and choline) induce permanent changes in DNA methylation, gene expression, and later phenotype in the offspring[19][20][21]. Epigenetic studies applied to DOHaD in humans are limited but maternal periconceptal micronutrient supplementation has been shown to influence gene-specific differences in DNA methylation at birth[22] , and DNA methylation at birth has been related to later body size and adiposity[23][24]. The timing of conception (by season) has also been shown to influence DNA methylation patterns with conception during rainy season resulting in greater methylation thereby suggesting environmental variations have an influence.

Implications for prevention and policy

Maternal nutrition may be the single most important entity that permanently alters the structure and functional abilities of the fetus to cope with adverse environmental conditions in later life. Both undernutrition and overnutriton during intra-uterine life lead to similar risk profiles, suggesting that these conditions represent two sides of the same coin. In populations undergoing rapid economical and demographic changes, there is a double burden of maternal under-nutrition and over-nutrition. Maternal under-nutrition is associated with low birthweight, metabolic incompetence and insulin resistance (‘nutrient-mediated teratogenesis’). If fetal under-nutrition is followed by rapid childhood weight gain, the result is excess adiposity and a further increase in insulin resistance. In women, this leads to gestational diabetes, which exposes the fetus to ‘fuel-mediated teratogenesis’ and exacerbates diabesity in the next generation[25] (Figure 4). Figure 4: (Click to enlarge)Nutritional transitions causing disease - double burden of under and over nutrition. Both undernutrition and rapid transition to an overnourished state influence the future risk of developing T2DM; preventive measures should address breaking the cycle at an earlier stage [25]
Figure 4: (Click to enlarge)Nutritional transitions causing disease - double burden of under and over nutrition. Both undernutrition and rapid transition to an overnourished state influence the future risk of developing T2DM; preventive measures should address breaking the cycle at an earlier stage [25]
The DOHaD hypothesis suggest several potential ways to break this intergenerational transmission: improving the nutrition of pregnant women, intervening in adolescence or the peri-conceptional period, or optimising nutrition to achieve good linear growth in infancy and/or prevent excessive childhood adiposity. These can cover a range of issues including age at marriage and conception, pre-pregnancy nutrition and metabolism, immunization, reduction of stress, food fortification, supplements, and treatment of existing conditions.

The field of DOHaD has now moved on to pre-conceptional intervention studies involving food-based and tablet-based micronutrient supplementation of women before and during pregnancy. The results of these trials will have significant implications for public health policy, and if successful, they offer, for the first time, a primordial prevention approach to reduce and halt the epidemic of T2DM.

References

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  2. ^ Hales CN, Barker DJP, Clark PMS, Cox LJ, Fall CHD. Fetal and infant growth and impaired glucose tolerance at age 64 years. BMJ 1991; 303:1019-22.

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