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Diabetes has become a global public health problem due to its increasing number of incidence all over the world. The number of children and adolescents affected by type 2 diabetes is also increasing. Low birth weight, defined as a weight of less than 2500 g irrespective of gestational age, has been hypothesized to have association with type 2 diabetes in later life. However, the explanation of the possible mechanisms of this relationship is still unclear. This review was purposed to carry out a systematic evaluation of published studies reporting on association between low birth weight and type 2 diabetes in children and adolescents. The possible mechanisms that were proposed to link low birth weight with type 2 diabetes are through defective β-cells growth and function, insulin resistance, alteration in intrauterine insulin secretion or action produced by genetic variants and increasing risk of obesity and central adiposity.
Diabetes has become a global public health problem due to its increasing number of incidence all over the world. It is predicted that in 2030 there will be 552 million people with diabetes.1 Although the greatest number of people with diabetes are adults, the number of effected children and adolescents is also increasing. Children with diabetes will potentially develop complications earlier as young adults, therefore the burden of this disease will significantly influence the society. Among these children, most of them are diagnosed as type 1 diabetes, still the number of type 2 diabetes in children is also increasing.1
Low birth weight, defined as a weight of less than 2500 g irrespective of gestational age, has been hypothesized to have correlation with type 2 diabetes in later life.2 The explanation of the mechanistic basis of this relationship is still unclear. One possible mechanism is poor gestational environment, for which low birth weight is surrogate, results as insulin resistance with its metabolic disturbances.3-4 Insulin resistance is inability of the existing insulin to increase glucose uptake and its utilization in an individual as much as it does in a normal population.5 The level of insulin may be normal or even high. On the other hand, some studies have shown that low birth weight is associated with dysfunction of β-cell pancreas that produce insulin.6 This impairment results as lack of insulin level which is contrary with the one in insulin resistance. Eventually, epidemiologic investigations also found that low birth weight was associated with obesity in later life, which has been identified as a strong risk factor for type 2 diabetes.7 This implies that low birth weight is indirectly related to type 2 diabetes through obesity development.
Studies conducted to examine the link between low birth weight and type 2 diabetes are mostly done in adults.8 As the incidence of type 2 diabetes in children and adolescents is increasing, the effect of low birth weight on risk of type 2 diabetes may also have occurred earlier in life. The mechanisms of linking low birth weight and type 2 diabetes in children and adolescents may be differ from that in adults since understanding the underlying mechanism may potentially be misled by accumulation of post-natal risk factors over time. This review will carry out a systematic evaluation of published studies reporting on association between low birth weight and type 2 diabetes in children and adolescents to establish the overall strength, consistency and independence of the association.
Thrifty phenotype hypothesis
Thrifty phenotype hypothesis was proposed almost 2 decades ago by Hales and Baker (1992) as hypothesis of the etiology of type 2 diabetes. The hypothesis' main idea is that nutritional insufficiency condition that exposed a fetus in the womb and shortly after birth will be unfavorable to the development and function of pancreas, in particular β-cells of the islets of Langerhans.2 The development of this β-cells progresses promptly during fetal life and early infancy. Undernourished condition during pregnancy and first year of age could irreversibly impair the organs and tissues in terms of size and structure, which then will affect the function. Thus impaired glucose tolerance/type 2 diabetes is predicted as a result from the negative influences on growth at early life.
The thrifty phenotype hypothesis suggests that impaired early growth of islets of Langerhans and β-cells is a key element in the etiology of type 2 diabetes.2 This abnormal condition is not merely on the lack number of β-cells but the cells may also have been altered, or other features of its complex structure and function, like vascularization and innervation may also have been impaired during the development.
Reduced state of β-cells that leads to diabetes will only occur when the individual has a sudden move to normal or even overnutrition where much insulin production is needed.
Key explanations for the thrifty phenotype hypothesis are as follow:
Deficiency of β-cells in type 2 diabetes
The situation that in type 2 diabetes there was reduced number and total area of islet of Langerhans was used to support the thrifty phenotype hypothesis.2 But recent studies suggested that the decrease is acquired over time as the type 2 diabetes develops.9-14 The β-cells loss and onset of type 2 diabetes are mainly due to the increase of β-cells apoptosis caused by disease progressivity and glucotoxicity.9, 15
Degree of deficiency of β-cells required to reduce glucose tolerance
The degree of deficiency of β-cells required to reduce glucose tolerance is remain uncertain. A study in people that underwent hemipancreactectomy for purpose of pancreas donation in 1997-2003 have shown that 6 out of 15 participants had normal blood glucose level.16 There is a capability to maintain the normal glucose tolerance in approximately 50% of remaining β-cells. Another study found that deficit of approximately 50 and 65% of β-cells would lead to impaired fasting glucose and type 2 diabetes, respectively.17
Major nutritional determinants of fetal growth
Protein, in particular amino acids, has been indicated as the major nutritional determinants of fetal growth.18 Thus, it is important to understand what effect amino acids have on the development and growth of β-cells in the fetus. In an animal study, low protein during gestation has found to have adverse effects on glucose metabolism, resulting in insulin resistance in adult offspring.19 L-arginine, which is an amino acid, is revealed to be essential for pancreatic β-cells functional integrity and metabolism.20
Amino acid supply is abnormal in growth retarded babies
A previous study using animal models has proven that maternal low protein diet led to intra-uterine growth retardation (IUGR) of the offsprings.21 The study also found that methionine and glycine have important role in formation of nucleic acid, collagen and heme.
Defective β-cells growth and function result from malnutrition
Using a rat model, a study found that under nutrition during last week of pregnancy (restriction to 40-50% of normal intake) was a risk for developing of low β-cells mass and low β-cells neogenesis that will lead to impaired function of the β-cells.17 This condition remains to adulthood as reduced β-cells mass and insulin content. If the under nutrition continues to the early postnatal, the reduction of β-cells mass is permanent with loss of glucose tolerance in adulthood as the consequence.
Several studies, done in children age 5-15 years old in different places, show that insulin resistance is related to low birth weight.22-23 One study even found the dose response relationship between reduction in birth weight and increasing of insulin resistance.22 On the other hand, as number of low birth weight is decreased in developed country, a study done in 5-year-old children in UK found that insulin resistance was not related to birth weight but was correlated with current weight and weight catch-up in both sexes.4
Mechanism that may explain the association between birth weight and insulin resistance is that suboptimal nutrition during pregnancy will reduce the proportion of fetus lean mass relative to body fat.22 As the consequence and a way of adaptation from this condition, insulin resistance will occur. Other kind of adaptation that will happen during organ development process with restricted nutrition is that the nutrients will be distributed selectively for most vital organ development such as brain (brain sparing). The other 'less vital' organs such as skeleton, liver, β-cells mass of pancreas and blood vessels then will have impaired development.
Insulin resistance is also strongly associated with body mass index in all children and height in the pre-pubertal age group. Another dose-response relationship is found linking birth weight, body mass index, height in pre-pubertal age and insulin resistance. Children who have less birth weight but more body mass index and height (in pre-pubertal age) were most insulin resistance.23
Birth weight also has negative relationship with waist circumference in children.22 In other words, low birth weight infants tend to have higher waist circumference when grow up. As insulin resistance in adult is positively related to waist circumference, there is also similar relationship in children.22 Brain sparing mechanism that is explained above also plays a role. A positive energy balance would be resulted from saving the energy to maintain brain development and functioning. Later in life, this positive energy balance would lead to fat accumulation, particularly in the abdominal region. This centralization of adiposity consists of a substrate enabling metabolic speed in providing glucose through stress-related metabolic pathways, with the aim of maintaining adequate glucose levels, particularly in the brain.22
Fetal insulin hypothesis
Fetal insulin hypothesis was first introduced by Hattersley et al in 1999. This alternative hypothesis stated that reduce birth weight might have been caused by alteration in intrauterine insulin secretion or action produced by genetic variants predisposing to type 2 diabetes.24 A more recent study done by Freathy has successfully shown the link between 2 recently identified type 2 diabetes loci (CDKAL1 and HHEX-IDE) and reduce birth weight by examining fetal DNA from 7,986 mothers and 19,200 offspring from 4 European studies.25 They found that in carriers of 4 type 2-diabetes risk alleles there was a mean difference of 80 g in birth weight compared to individuals carrying none of these risk alleles. The risk of developing type 2 diabetes may still be influenced by insufficient insulin secretion later in life.
Fetal growth is significantly determined by fetal insulin secretion that does its main function in the third trimester when the fetus greatest weight gain occur.24 The important role of insulin can be seen clearly in giant babies born to mothers with gestational diabetes. This macrosomia was mediated indirectly by increased fetal insulin secretion in response to fetal sensing of maternal hyperglycaemia rather than as a consequence of direct increase in the transfer of nutrients.
Low birth weight and obesity
Low birth weight infants tend to have higher obesity incidence during childhood compared to the normal birth weight ones, with prevalence varies by birth weight category.7 This condition possibly occurred because of hypothalamic nuclei dysfunction that controlled energy balance.26 A better metabolic efficiency to compensate for the energetic shortage will be created on condition of undernutrition during first months of gestation, when central nervous system development takes place. When enough food is available, this acquired energy-sparing system would lead to an excessive fat storage. 26
Besides the timing on maternal malnutrition, the postnatal environment also have effect on the programming of obesity during fetal and early postnatal life.27 Increase in obesity was mainly found when infants have been malnourished during the first trimester but then have early catch-up growth after birth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favorable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis).27
Below is the list of studies that have been included in this review with their levels of evidence and Hill's criteria:
Type of Study
Levels of Evidence
Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis
Hales et al
Consistency, plausible biology mechanism, temporal relationship
Protein restriction during gestation and/or lactation causes adverse trangenerational effects on biometry and glucose metabolism in F1 and F2 progenies of rats*
Pinheiro et al
Plausible biology mechanism, coherence with laboratory findings, temporal relationship
Early-life origins of type 2 diabetes: fetal programming of the Beta-cell mass*
Portha et al
Review on animal studies
Consistency, plausible biology mechanism, coherence with laboratory findings, temporal relationship
The relationship between birth weight and insulin resistance in childhood
Lemos et al
Dose response relationship, temporal relationship
The association of birthweight and contemporary size with insulin resistance among children from Estonia and Denmark: findings from the European Youth Heart Study
Plausible biology mechanism, temporal relationship
The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease
Hattersley et al
Plausible biology mechanism, temporal relationship
Type 2 diabetes risk alleles are associated with reduced size at birth
Freathy et al
Plausible biology mechanism, dose response relationship, temporal relationship
Evolution of obesity in a low birth weight cohort
Casey et al
Consistency, temporal relationship
Programming towards childhood obesity.
Consistency, plausible biology mechanism, temporal relationship
Grades of recommendations
*From animal studies, just to show the plausible biological mechanism for Hill's criteria
Based on review from these published studies that investigated association between low birth weight and type 2 diabetes in children and adolescents, it can be concluded that low birth is associated with type 2 diabetes in children and adolescents. The possible mechanisms that link low birth weight and type 2 diabetes in children and adolescents were through defective β-cells growth and function, insulin resistance, alteration in intrauterine insulin secretion or action during fetal growth that produced by common genetic variants and increasing risk of obesity and central adiposity.
Public Health Impact
Type 2 diabetes has an increasing incidence in children and adolescents. Children with diabetes will potentially develop complications earlier as young adults, therefore the burden of this disease will significantly influence the society. Prevention of low birth weight, that might play role as a risk factor in developing type 2 diabetes in children and adolescents, is required.
In areas like developing countries where low birth weight is still common, public health policies that embrace preventive strategy to promote adequate maternal-fetal and child development is necessary. Interventions undertaken in pregnancy might be of benefit to the health of the offspring later in life. While in developed countries, with the great majority of children being not predisposed to low birth weight, prevention strategies should not be addressed to the whole pediatric population but targeted to those at risk such as low socio-economic population as well as smoking and alcohol drinking women with productive age.