Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat

  1. Doris A. Stoffers1,
  2. Biva M. Desai1,
  3. Diva D. DeLeon12 and
  4. Rebecca A. Simmons3
  1. 1Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  2. 2Division of Pediatric Endocrinology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  3. 3Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

    Abstract

    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 β-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 β-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 β-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.

    Footnotes

    • Address correspondence and reprint requests to Doris A. Stoffers, MD, PHD, Clinical Research Building 611B, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104. E-mail: stoffers{at}mail.med.upenn.edu.

      Received for publication 2 August 2002 and accepted in revised form 3 December 2002.

      D.S. holds stock in and has received honoraria from Amylin.

      Ex-4, Exendin-4; GLP-1, glucagon-like peptide-1; IUGR, intrauterine growth- retarded; PD, postnatal day; PDX, pancreatic duodenal homeobox; Ppx, partial pancreatectomy; STZ, streptozotocin.

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