The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition?

Abstract. Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l^-1), than in either the SGA group (n= 22, 31·4±3·5 μg l^-1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l^-1, P= 0·0001). IGFBP-3 showed similar changes (UPI: 682·6±50·0 μg l^-1; SGA: 831·9±55·5 μg l^-1; AGA: 847·7±19·8 μg l^-1). In contrast, IGFBP-1 levels were significantly higher in the UPI group (312·4±57·5 μg l^-1) than in either the SGA group (132·6±39·5 μg l^-1, P= 0·009) or the AGA group (116·9±25·4 μg l^-1, P= 0·003), and the normal inverse relationship between IGFBP-1 and insulin levels was lost in the UPI group. IGFBP-2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l^-1; SGA: 878·5±80·3μg l^-1, P= 0·0001; AGA: 791·6±27·0 μg l^-1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.