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

Low birthweight is associated with insulin resistance, hypertension, corona ry-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 in sulin resistance results In impaired insulin-mediated growth in the fetus a s well as insulin resistance In adult life. Low birthweight, measures of in sulin resistance in life, and ultimately glucose intolerance, diabetes, end hypertension could all be phenotypes of the same insulin-resistant genotyp e. There is evidence to support this hypothesis. Insulin secreted by the fe tal pancreas in response to maternal glucose concentrations is a key growth factor. Monogenic diseases that impair sensing of glucose, lower insulin s ecretion, 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 v ascular development during fetal life and early childhood, as a result of g enetic insulin resistance, could also explain the increased risk of hyperte nsion and vascular disease. The predisposition to NIDDM and vascular diseas e is likely to be the result of both genetic and fetal environmental factor s.