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 day 1-6 of life. Hyperinsulinemic-euglycemic clamp studies and Dexa scans were performed and triglyceride content, MnSOD, GSH/GSSG, and TBAR levels, insulin stimulated IRS-2 and Akt-2 phosphorylation were measured in liver at 8-weeks of age and in Ex-4 treated newborn hepatocytes. 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.