Journal.

HYPOTHESIS

Hypothesis

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

Andrew T Hattersley, John E Tooke Low birthweight is associated with insulin resistance, hypertension, coronary-artery disease, and non-insulindependent 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. One of the most stimulating clinical observations in the past decade has been the association between low birthweight and hypertension, coronary-artery disease, and non-insulin-dependent diabetes (NIDDM) in adult life.1–3 Further studies in both children and adults of various races have shown a consistent association between features suggesting impaired fetal growth and measures of insulin resistance.4–7 This association has been attributed to a...