Developmental origins of beta-cell failure in type 2 diabetes: the role of epigenetic mechanisms.
Intrauterine growth retardation (IUGR) has been linked to later development of type 2 diabetes in adulthood. An abnormal metabolic intrauterine milieu affects the development of the fetus by permanently modifying gene expression of susceptible cells. Altered gene expression persists after birth, suggesting that an epigenetic mechanism may be responsible for changes in transcription. Uteroplacental insufficiency (IUGR) is associated with hypomethylation and hyperacetylation of genomic DNA in brain and liver of IUGR fetal and juvenile rats. These findings are associated with zinc deficiency that often accompanies fetal growth retardation. Studies in the IUGR rat also demonstrate that an abnormal intrauterine environment induces epigenetic modifications of key genes regulating beta-cell development and experiments directly link chromatin remodeling to suppression of transcription. Dietary protein restriction of pregnant rats causes fetal growth retardation and is associated with hypomethylation of the glucocorticoid receptor (GR) and PPARgamma genes in liver of the offspring. It is postulated that these epigenetic changes result in the observed increase in gene expression of GR and PPARgamma. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring.
Simmons
Rebecca A
RA
Department of Pediatrics Children's Hospital Philadelphia, University of Pennsylvania, PA 19104, USA. rsimmons@mail.med.upenn.edu
D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D009752:Nutritional Status; D010927:Placental Insufficiency; D011247:Pregnancy; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D011965:Receptors, Glucocorticoid