062. DEVELOPMENTAL ORIGINS OF TYPE 2 DIABETES: EPIGENETIC MECHANISMS IN BETA CELL FAILURE

Abstract

The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic b -cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR and epigenetic modifications are responsible for this decrease. Exendin-4 (Ex-4), a long-acting glucagon-like peptide 1 (GLP-1) analog, given on days 1-6 of life increases Pdx1 expression and prevents the development of diabetes in the IUGR rat. Here we show that Ex-4 increases USF-1 and PCAF association at the proximal promoter of Pdx1, thereby increasing histone acetyl transferase (HAT) activity leading to a permanent increase in histone H3 acetylation and H3K4 methylation. Normalization of these histone modifications precludes DNA methylation thereby preventing silencing of Pdx1 in islets of IUGR animals. These studies demonstrate a novel mechanism whereby a short treatment course of Ex-4 in the newborn period prevents diabetes in adulthood by restoring Pdx1 promoter chromatin structure thus preserving Pdx1 transcription.