Developmental Origins of β-Cell Failure in Type 2 Diabetes: The Role of Epigenetic Mechanisms

Abstract

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 ␤-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 PPAR␥ genes in liver of the offspring. It is postulated that these epigenetic changes result in the observed increase in gene expression of GR and PPAR␥. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring. A n adverse intrauterine milieu impacts the development of the fetus by modifying gene expression in both pluripotential cells or terminally differentiated, poorly replicating cells. The long-range effects on the offspring (into adulthood) depend upon the cells undergoing differentiation, proliferation, and/or functional maturation at the time of the disturbance in maternal fuel economy. Permanent alterations to the phenotype of the offspring suggest that fetal growth retardation is associated with stable changes in gene expression. In this article, a general review of epigenetics will be provided and the possible causal role of chromatin remodeling in the development of type 2 diabetes will be discussed. CHROMATIN STRUCTURE, DNA METHYLATION, AND GENE EXPRESSIONEpigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene activity states from one generation of cells to the next. Excellent reviews on this topic appear frequently, reflecting the rapid advances of knowledge in the field (1-4). Epigenetic states can be modified by environmental factors, which may contribute to the development of abnormal phenotypes. There are at least two distinct classes of epigenetic information that can be inherited with chromosomes. One class of epigenetic control of gene expression involves changes in chromatin proteins, usually involving modifications of histone tails. In eukaryotes, DNA is assembled with histones to form the nucleosome, in which DNA is wrapped approximately two turns around an octameric complex composed of two molecules of each of the four histones H2A, H2B, H3, and H4. The amino termini of histones can be modified by acetylation, methylation, sumoylation, phosphorylation, g...

Significance of DNA methyltransferase-1 and histone deacetylase-1 in pancreatic cancer

“…In this study, we did not find a significant correlation between DNMT1 expression and proliferative activity, as indicated by the proliferative labeling results of Ki67 and PCNA. Recently, several studies identified a role for environmental factors in regulating epigenetic modifications (39)(40)(41)(42). Our analysis of the correlation between patient life styles, such as smoking and alcohol consumption, and the expression of DNMT1 and HDAC1, showed no significance.…”

The social environment and the epigenome

“…alteration in DNA methylation. It is also widely accepted that chemicals as well as altered dietary intake would affect DNA methylation during gestation [Simmons, 2007] especially during gametogenesis [Anway et al, 2005] at a point when methylation machineries are highly active and cells are undergoing rapid cell division. It is difficult to accept however that environmental agents could affect DNA methylation patterns throughout life well after tissues and organs are formed and their methylation pattern is established.…”

Genetics of Type 2 Diabetes

“…In the pathogenesis of T2D, special attention has been given to the role of intrauterine DNA methylation and imprinting for the programming of diabetogenic effects later in life (103 ). An interesting study by Dabelea et al has shown that intrauterine exposure to diabetes increases the risk of diabetes and obesity in the offspring compared to siblings who were born before their mothers' onset of diabetes (104 ).…”