Exendin-4 normalizes islet vascularity in intrauterine growth restricted rats: potential role of VEGF.

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in beta-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of beta-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p = 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of beta-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of beta-cell mass and as a potential therapeutic target for diabetes prevention.