Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency is a common complication of pregnancy and leads to an increased risk for type 2 diabetes (T2D) in adulthood. We model IUGR by performing bilateral uterine artery ligation in pregnant rats at d18 of gestation (term 22 days). Offspring are growth restricted and newborn males, but not females have decreased ß-cell proliferation and impaired insulin secretion which is associated with inflammation and increased IL-4 levels. IUGR males develop obesity and insulin resistance in adulthood. Neutralizing IL-4 antibody given on postnatal days 1-6 normalizes hyperglycemia in adult IUGR animals. The aim of this study was to determine whether IL-4 is sufficient to recapitulate the IUGR phenotype. IL-4 (50ng or 100ng) or PBS was injected subcutaneously to normal newborn rat pups on postnatal days 1-6. IL-4 had no adverse effects on newborn rat pups and weights did not differ between the IL-4 and PBS injected pups (n=15). IL-4 injection had no effect on insulin secretion as measured by both static incubation experiments and perifusion square wave studies (n=6). Surprisingly, at P14, animals treated with IL-4 in the newborn period had decreased body fat content (p=0.0173) compared to controls (n=6). Further, at 7 weeks of age IL-4 injected rats weighed less than controls (n=7; p=0.00017) and the weight difference increased with age. At 10 weeks, IL-4 injected rats had decreased fasting blood glucose levels (n=6-7; p=0.0055) and improved glucose tolerance and the area under the curve (AUC) was less than controls (n=3; p=0.0513). These results suggest that IL-4 is not sufficient to recapitulate the IUGR metabolic phenotype. However, IL-4 administered transiently during the neonatal period has lasting effects in adulthood, decreasing fat content and improving glucose tolerance.
T. Ying: None. R.A. Simmons: None.
National Institutes of Health