Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1785-94. doi: 10.1152/ajpregu.00519.2009. Epub 2009 Oct 21.


Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagon-like-peptide-1 agonist, exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given exendin-4 on days 1-6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Aging
  • Animals
  • Animals, Newborn
  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Body Composition
  • Body Weight
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Disease Models, Animal
  • Drug Administration Schedule
  • Exenatide
  • Female
  • Fetal Growth Retardation / drug therapy*
  • Fetal Growth Retardation / metabolism
  • Fetal Growth Retardation / physiopathology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucokinase / genetics
  • Glucose-6-Phosphatase / genetics
  • Hypoglycemic Agents / administration & dosage*
  • Injections, Subcutaneous
  • Insulin / blood
  • Insulin Resistance*
  • Liver / drug effects*
  • Liver / metabolism
  • Oxidative Stress / drug effects*
  • Peptides / administration & dosage*
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Pregnancy
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Venoms / administration & dosage*


  • Biomarkers
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • RNA, Messenger
  • Venoms
  • Exenatide
  • Glucokinase
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (GTP)