Exendin-4 Normalizes Islet Vascularity in Intrauterine Growth Restricted Rats: Potential Role of VEGF

• Published in: Pediatric research Vol. 66; no. 1; pp. 42 - 46
• Main Authors: Ham, J Nina, Crutchlow, Michael F, Desai, Biva M, Simmons, Rebecca A, Stoffers, Doris A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2009; Lippincott Williams & Wilkins
• Subjects: Animals; basic-science-investigation; Biological and medical sciences; Blood Vessels - drug effects; Blood Vessels - growth & development; Blotting, Western; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - prevention & control; DNA Primers - genetics; Female; Fetal Growth Retardation - metabolism; Fetal Growth Retardation - physiopathology; Gene Expression Regulation - drug effects; General aspects; Immunohistochemistry; Islets of Langerhans - blood supply; Islets of Langerhans - drug effects; Medical sciences; Medicine; Medicine & Public Health; Pediatric Surgery; Pediatrics; Peptides - administration & dosage; Peptides - pharmacology; Peptides - therapeutic use; Pregnancy; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A - metabolism; Venoms - administration & dosage; Venoms - pharmacology; Venoms - therapeutic use; Pediatrics; Rat; Growth; Rodentia; Langerhans islet; Exenatide; In utero; Glucagon like peptide 1; Vertebrata; Hypoglycemic agent; Gastrointestinal hormone; Mammalia; Vascular endothelium growth factor; Uterus; Analog; Animal; Female genital system; Endocrine pancreas
• DOI: 10.1203/PDR.0b013e3181a282a5
• EISSN: 1530-0447
• ISSN: 0031-3998

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 β-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of β-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 β-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 β-cell mass and as a potential therapeutic target for diabetes prevention.