THE PATHOPHYSIOLOGY OF THE INSULIN-LIKE GROWTH-FACTOR AXIS IN FETAL GROWTH FAILURE - A BASIS FOR PROGRAMMING BY UNDERNUTRITION

Recent evidence suggests that a number of adulthood conditions, includ ing non-insulin dependent diabetes mellitus (NIDDM) and lipid and card iovascular abnormalities are associated with intra-uterine growth reta rdation (IUGR). It is possible that this arises from programming of en docrine axes during development as a result of an adverse intra-uterin e environment. Insulin-like growth factors (IGFs) are mitogenic polype ptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are mo dulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 i s 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 cordocent esis we have investigated the role of the IGF/IGFBP axis in human feta l development. In a study of 130 singleton pregnancies we have examine d 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-I was significantly low er in the UPI group (n = 14, 7.8 +/- 0.6 mu g l(-1)), than in either t he SGA group (n = 22, 31.4 +/- 3.5 mu g l(-1), P = 0.0001) or the AGA group (n = 94, 36.3 +/- 1.9 mu g l(-1), P = 0.0001). IGFBP-3 showed si milar changes (UPI: 682.6 +/- 50.0 mu g l(-1) SGA: 831.9 +/- 55.5 mu g l(-1); AGA: 847.7 +/- 19.8 mu g l(-1)). In contrast, IGFBP-1 levels w ere significantly higher in the UPI group (312.4 +/- 57.5 mu g l(-1)) than in either the SGA group (132.6 +/- 39.5 mu g l(-1), P = 0.009) or the AGA group (116.9 +/- 25.4 mu g l(-1), P = 0.003), and the normal inverse relationship between IGFBP-1 and insulin levels was lost in th e UPI group. IGFBP-2 levels showed a similar pattern (UPI: 2510.3 +/- 178.0 mu g l(-1); SGA: 878.5 +/- 80.3 mu g l(-1), P = 0.0001; AGA: 791 .6 +/- 27.0 mu g 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 undernutritio n, may be important in the pathogenesis of disease in adulthood.