The fetal insulin hypothesis: an alternative explanation of the association of low bir thweight with diabetes and vascular disease

doi:10.1016/S0140-6736(98)07546-1

The Lancet

Volume 353, Issue 9166, 22 May 1999, Pages 1789-1792

https://doi.org/10.1016/S0140-6736(98)07546-1 Get rights and content

Summary

Low birthweight is associated with insulin resistance, hypertension, coronary-artery disease, and non-insulin-dependent diabetes (NIDDM). A suggested explanation for this association is intrauterine programming in response to maternal malnutrition. We propose, however, that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus as well as insulin resistance in adult life. Low birthweight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension could all be phenotypes of the same insulin-resistant genotype. There is evidence to support this hypothesis. Insulin secreted by the fetal pancreas in response to maternal glucose concentrations is a key growth factor. Monogenic diseases that impair sensing of glucose, lower insulin secretion, or increase insulin resistance are associated with impaired fetal growth. Polygenic influences resulting in insulin resistance in the normal population are therefore likely to result in lower birthweight. Abnormal vascular development during fetal life and early childhood, as a result of genetic insulin resistance, could also explain the increased risk of hypertension and vascular disease. The predisposition to NIDDM and vascular disease is likely to be the result of both genetic and fetal environmental factors.

Section snippets

The fetal insulin hypothesis

We propose that the association between low birthweight and adult insulin resistance is principally genetically mediated. Genetically determined insulin resistance could result in low insulin-mediated fetal growth in utero as well as insulin resistance in childhood and adulthood (figure 1). Low birthweight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension, would all be phenotypes of the same insulin-resistant genotype. Central to this fetal

Role of fetal insulin in fetal growth

Fetal insulin secretion is one of the key determinants of fetal growth, acting mainly in the third trimester when the weight of the fetus increases greatly. The clearest clinical demonstration of the role of insulin is the macrosomic children born to women with diabetes in pregnancy. Pedersen¹⁰ proposed that this macrosomia did not result from a direct increase in the transfer of nutrients but was mediated indirectly by increased fetal insulin secretion in response to fetal sensing of maternal

Low birthweight and insulin resistance in childhood and adulthood

The monogenic diseases described establish the principle of the role of fetal genetic influences. However, because they are rare, they cannot explain the variation in birthweight seen in the normal population. According to the fetal insulin hypothesis, common, as yet undefined, polygenic genetic factors that increase insulin resistance, both in utero and in adult life, would produce two phenotypes—a small, thin baby and an adult with insulin resistance and increased risk of hypertension and

Testing the hypothesis

Both the fetal programming proposed by Barker and colleagues and our fetal insulin hypothesis provide plausible explanations for the associations seen between fetal growth and adult disease, and both are likely to have a role. To test whether genetic factors have an important role, we propose the following experiments.

According to the fetal insulin hypothesis, the size of the baby will be influenced by inherited paternal genetic factors in addition to inherited maternal genetic factors and the

Conclusion

The fetal insulin hypothesis offers an alternative explanation for the consistent association between impaired fetal growth and insulin resistance during life and the link with hypertension and vascular disease. A large component of variation in fetal weight may be explained by genetic control in the fetus of glucose sensing, insulin secretion, and insulin resistance. We suspect that the most important of these is insulin resistance, since this factor shows the most variation within the normal

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Metabolic syndrome, a clustering of cardiometabolic risk factors, is reportedly the most common precursor of type 2 diabetes and cardiovascular disease. Epidemiological and experimental evidence strongly suggest that unbalanced maternal nutrition causes permanent effects on physiological systems of the developing fetus (“programming”), predisposing them to increased risk of non-communicable disease. The Developmental Origins of Health and Disease (DOHaD) model combines post-natal environmental insults to fetal programming to describe lifetime trajectories of health and disease. Birth cohort studies in India have provided evidence that both maternal undernutrition and overnutrition increase the risk of metabolic syndrome risk in the offspring (“Dual-teratogenesis”). These studies show that maternal nutrient imbalance of vitamins (vit B12, vit D, and folate) and maternal diabetes influence offspring birth size and body composition and postnatal growth trajectory which in turn predict adiposity, insulin resistance, and metabolic syndrome. The characteristic Indian “thin-fat” phenotype is thought to be a consequence of fetal programming of body composition and may underlie the high disease susceptibility. Epigenetic basis of these findings is being evaluated. Pre-conceptional intervention studies have provided initial evidence for a causal association for nutritional programming in India. Future analyses of these studies will help elucidate mechanisms and could provide a key to successful interventions for primordial prevention of metabolic syndrome.
Abnormalities of Fetal Growth
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Normal fetal growth is determined by a number of factors, including genetic potential, the ability of the mother to provide sufficient nutrients, the ability of the placenta to transfer nutrients, and intrauterine hormones and growth factors. The pattern of normal fetal growth involves rapid increases in fetal weight, length, and head circumference during the last half of gestation. During the final trimester, the human fetus accumulates significant amounts of fat. The birth weight for gestational measurements among populations have been shown to increase over time, and thus, standards for normal fetal growth require periodic reevaluation for clinical relevance. These increases in birth weight for gestational age over time are attributed to improvements in living conditions and maternal nutrition and changes in obstetric management. Variations in fetal growth have been identified in diverse populations and are associated with geographic locations (sea level versus high altitude), populations (white, African-American, Latino), maternal constitutional factors, parity, maternal nutrition, fetal gender, and multiple gestations. In this chapter, we discuss these factors in greater detail, and critically review the long-term effects of abnormal fetal growth.
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Adiposity is an established risk factor for pediatric nonalcoholic fatty liver disease (NAFLD), but little is known about the influence of body composition patterns earlier in life on NAFLD risk.
We aimed to examine associations of body composition at birth and body composition trajectories from birth to early childhood with hepatic fat in early childhood.
Data were from the longitudinal Healthy Start Study in Colorado. Fat-free mass index (FFMI), fat mass index (FMI), percentage body fat (BF%), and BMI were assessed at birth and/or ∼5 y in >1200 children by air displacement plethysmography and anthropometrics. In a subset (n = 285), hepatic fat was also assessed at ∼5 y by MRI. We used a 2-stage modeling approach: first, we fit body composition trajectories from birth to early childhood using mixed models with participant-specific intercepts and linear slopes (i.e., individual deviations from the population average at birth and rate of change per year, respectively); second, associations of participant-specific trajectory deviations with hepatic fat were assessed by multivariable-adjusted linear regression.
Participant-specific intercepts at birth for FFMI, FMI, BF%, and BMI were inversely associated with log-hepatic fat in early childhood in models adjusted for offspring demographics and maternal/prenatal variables [back-transformed β (95% CI) per 1 SD: 0.93 (0.88, 0.99), 0.94 (0.88, 0.99), 0.94 (0.89, 0.99), and 0.90 (0.85, 0.96), respectively]. Whereas, faster velocities for BF% and BMI from birth to ∼5 y were positively associated with log-hepatic fat [back-transformed β (95% CI) per 1 SD: 1.08 (1.01, 1.15) and 1.08 (1.02, 1.15), respectively]. These latter associations of BF% and BMI velocities with childhood hepatic fat were attenuated to the null when adjusted for participant-specific intercepts at birth.
Our findings suggest that a smaller birth weight, combined with faster adiposity accretion in the first 5 y, predicts higher hepatic fat in early childhood. Strategies aiming to promote healthy body composition early in life may be critical for pediatric NAFLD prevention. This study was registered voluntarily at clinicaltrials.gov as NCT02273297.
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The aim was to investigate the independent relevance of genetic predisposition to low birth weight and childhood obesity for T2D, and their attenuation, by adherence to a healthy lifestyle in adulthood.
Genetic risk scores (GRSs) were estimated for birth weight and childhood BMI with genetic risk categories according to their quintiles in 90,029 and 321,225 participants from the China Kadoorie Biobank (CKB; mean age, 53.0 y) and UK Biobank (UKB; 56.1 y). Healthy lifestyle scores were defined on noncurrent smoking, moderate alcohol consumption, healthy diet, regular physical activity, and nonobesity, and categorized into healthy (4∼5 factors), intermediate (2∼3 factors), and unhealthy (0∼1 factor) lifestyle.
GRSs for low birth weight and childhood BMI were associated with higher T2D risks. Healthy lifestyle was related to lower T2D risk, and there was an additive interaction with increasing childhood BMI GRS and decreasing healthy lifestyle factors on T2D risk, whereas no additive interaction was observed for birth weight. Participants with a healthy compared with an unhealthy lifestyle had a 68% (HR: 0.32; 95% CI: 0.22, 0.47) and 77% (0.23; 0.19, 0.28) lower T2D risk among participants at high genetic risk (lowest quintile) of low birth weight in the CKB and UKB. Among participants with high genetic risk (highest quintile) of childhood obesity, compared with those with an unhealthy lifestyle, adherence to a healthy lifestyle was associated with a 69% (0.31; 0.22, 0.46) and 80% (0.20; 0.17, 0.25) lower risk of T2D in the CKB and UKB.
Genetic predisposition to low birth weight and childhood obesity were associated with higher risk of adult T2D and these excess risks were attenuated by adherence to a healthy lifestyle in adulthood, particularly among those at high genetic risk of childhood obesity.
Birth weight and cardiometabolic risk factors: A discordant twin study in the UK Biobank
2023, Journal of Developmental Origins of Health and Disease

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HypothesisThe fetal insulin hypothesis: an alternative explanation of the association of low bir thweight with diabetes and vascular disease

Summary

Section snippets

The fetal insulin hypothesis

Role of fetal insulin in fetal growth

Low birthweight and insulin resistance in childhood and adulthood

Testing the hypothesis

Conclusion

Mol Med Today

J Pediatr

Fetal and placental size and risk of hypertension in adult life

BMJ

The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life

Paediatr Perinat Epidemiol

Fetal and infant growth and impaired glucose tolerance at age 64

BMJ

Fetal growth and impaired glucose tolerance in men and women

Diabetologia

Fetal growth and glucose and insulin metabolism in four-year-old Indian children

Diabet Med

Thinness at birth and glucose tolerance in seven-year-old children

Diabet Med

Relation between birth weight and the insulin sensitivity index in a population sample of 331 young, healthy Caucasians

Am J Epidemiol

The pathogenesis of NIDDM

Diabetologia

Hyperglycaemia-hyperinsulinism theory and birthweight

Cesarean delivery in relation to birth weight and gestational glucose tolerance: pathophysiology or practice style? Toronto Trihospital Gestational Diabetes Investigators

JAMA

Relation of glucose tolerance to complications of pregnancy in nondiabetic women

N Engl J Med

The influence of maternal glucose metabolism on fetal growth, development and morbidity in 917 singlet on pregnancies in nondiabetic women

Diabetologia

Relation of birthweight to maternal plasma glucose and insulin concentrations during normal pregnancy

Diabetologia

Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes: the Toronto Tri-Hospital Gestational Diabetes Project

Am J Obstet Gynecol

Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus

N Engl J Med

Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations

J Clin Invest

Mutations in the glucokinase gene of the fetus result in reduced birth weight

Nat Genet

Pancreatic agenesis attributable to a single nucleotidedeletion in the human IPF1 gene coding sequence

Nat Genet

Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis

Am J Dis Child

Hypothesis
The fetal insulin hypothesis: an alternative explanation of the association of low bir thweight with diabetes and vascular disease