Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat.
Uteroplacental insufficiency resulting in fetal growth retardation is a common complication of pregnancy and a significant cause of perinatal morbidity and mortality. Epidemiological studies show an increased incidence of type 2 diabetes in humans who were growth retarded at birth. The mechanisms by which an abnormal intrauterine milieu leads to the development of diabetes in adulthood are not known. Therefore, a rat model of uteroplacental insufficiency was developed; intrauterine growth-retarded (IUGR) rats develop diabetes with a phenotype similar to that observed in the human with type 2 diabetes. We show here that administration of a pancreatic beta-cell trophic factor, exendin-4 (Ex-4), during the prediabetic neonatal period dramatically prevents the development of diabetes in this model. This occurs because neonatal Ex-4 prevents the progressive reduction in insulin-producing beta-cell mass that is observed in IUGR rats over time. Expression of PDX, a critical regulator of pancreas development and islet differentiation, is restored to normal levels, and islet beta-cell proliferation rates are normalized by the neonatal Ex-4 treatment. These results indicate that exposure to Ex-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of diabetes in adulthood.
Stoffers
Doris A
DA
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Clinical Research Building 611B, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA. stoffers@mail.med.upenn.edu
Desai
Biva M
BM
DeLeon
Diva D
DD
Simmons
Rebecca A
RA
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D000077270:Exenatide; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000150:complications* / Q000473:pathology; D015870:Gene Expression; D018149:Glucose Intolerance / Q000517:prevention & control; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins; D006706:Homeostasis; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage*; D010927:Placental Insufficiency / Q000150:complications*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics; D014688:Venoms
D001786:Blood Glucose; D018398:Homeodomain Proteins; D010455:Peptides; D012333:RNA, Messenger; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D000077270:Exenatide