Undernutrition before mating in ewes impairs the development of insulin resistance during pregnancy.

OBJECTIVE: To assess the effects of periconceptional undernutrition on maternal adaptation of insulin-dependent metabolism during pregnancy. METHODS: Romney ewes were randomly assigned to receive normal nutrition (n=12) or undernutrition before (from 60 days before until mating, n=7), after (2 days before to 30 days after mating, n=6) or before and after mating (from 60 days before to 30 days after mating, n=10). Insulin sensitivity was measured by hyperinsulinaemic-euglycaemic clamp at 65 days of gestation (term=147 days). Lamb growth rate was measured in late gestation by chronically implanted growth catheters and weight at 133 days of gestation. RESULTS: Ewes undernourished before or both before and after mating failed to develop the insulin resistance of pregnancy seen in normally nourished ewes. Ewes undernourished after mating showed intermediate insulin sensitivity. This was not related to plasma concentrations of pregnancy-related hormones, but was related to insulin kinetics. There was an inverse relationship between insulin sensitivity and fetal growth, with ewes that were most insulin sensitive having smaller, more slowly growing lambs (highest compared with lowest tertile for insulin sensitivity: fetal weight 3.5+/-0.3 compared with 4.5+/-0.1 kg, P=.02; growth rate 2.0+/-0.2 compared with 2.6+/-0.2 mm.day-1, P=.05). CONCLUSION: Maternal undernutrition before conception impairs adaptation of insulin-related metabolism during pregnancy in ways that affect fetal growth. This suggests a key mechanism whereby prepregnancy nutritional status influences pregnancy outcome.

Different periods of periconceptional undernutrition have different effects on growth, metabolic and endocrine status in fetal sheep.

Periconceptional undernutrition alters fetal growth and development. However, there are no data on separate effects of undernutrition before and after conception and few on underlying mechanisms. We determined the effects of mild periconceptional undernutrition on late gestation fetal growth, glucose-insulin axis, and maternal and fetal hypothalamic-pituitary-adrenal axes. Ewes were undernourished for 60 d before conception, 30 d after, or both, compared with well-nourished controls. Undernutrition before conception resulted in smaller, slower-growing fetuses with relatively larger placentae. Ewes that gained weight before, but lost weight after mating, or vice versa, had the smallest fetuses. Fetuses of ewes undernourished only before conception grew more slowly following instrumentation, and fetuses in both preconception undernutrition groups slowed their growth with a maternal fast. The fetal glucose-insulin axes and maternal and fetal hypothalamic-pituitary-adrenal axis were not different among groups. Maternal undernutrition at different periods around conception has different effects on fetal growth trajectory that are not reflected in size in late gestation. Preconceptional undernutrition alone alters fetal growth responses to late gestation stressors, suggesting that maternal nutrition is important at both times, and that fetal effects are neither due solely to substrate limitation, nor to excess fetal glucocorticoid exposure at the time of undernutrition.

C-type natriuretic peptide forms in the ovine fetal and maternal circulations: evidence for independent regulation and reciprocal response to undernutrition.

C-type natriuretic peptide (CNP) has a crucial role in postnatal endochondral bone growth and is rapidly responsive to changes in nutrition. Although CNP is expressed in the placenta, little is known about the regulation and role of CNP in fetal-maternal health. We hypothesized that CNP may be similarly responsive to undernutrition in the growing fetus, in which maternal nutrition is crucial to normal growth and development. We therefore studied maternal and fetal CNP and the aminoterminal (bioinactive) fragment of proCNP (NTproCNP) in 39 chronically catheterized pregnant sheep before and after a 3-d maternal fast from 121 d gestation. Maternal CNP and NTproCNP levels were higher than in the fetus (CNP 12-fold, NTproCNP 1.5-fold, both P < 0.001). The ratio of NTproCNP to CNP was higher in the fetus than the mother (53 +/- 3 vs. 8.7 +/- 0.6, P < 0.001), suggesting enhanced synthesis and/or degradation of CNP in the fetus. As in postnatal lambs, fetal plasma CNP forms fell promptly during maternal fasting. In contrast, maternal levels exhibited reciprocal and contemporaneous increase, which was reversed by refeeding. Uteroplacental production of CNP was suggested by a high venoarterial concentration gradient across the gravid uterus, and a correlation between maternal NTproCNP levels and placental weight (r(2) = 0.26, P = 0.01). These studies provide the first evidence that CNP is regulated independently in the fetus. Reciprocal increases in maternal CNP forms may reflect the response of the uteroplacental unit to substrate deficiency. CNP may have a role in maintaining fetal welfare and provides a possible marker of uteroplacental nutrient supply.