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