Intrauterine Growth Retardation - A Developmental Model of Type 2 Diabetes

Abstract

Intrauterine growth retardation has been linked to the development of type 2 diabetes later in life and the mechanisms underlying this phenomena are unknown. Epidemiological studies in humans show a distinct link with the exposure to an intrauterine insult that results in low birth weight and the development of type 2 diabetes in adulthood. Intrauterine growth retardation can be induced in rodent models by exposing the pregnant rat to a low protein diet, total calorie restriction, high dose glucocorticoids or inducing uteroplacental insufficiency, all which result in abnormalities in glucose homeostasis in the offspring later in life. Animal models of intrauterine growth retardation allow for a better characterization of changes in glucose homeostasis and corresponding changes in gene expression that can provide insight in the mechanisms by which intrauterine growth retardation leads to type 2 diabetes.

Figure 1

Summary of epigenetic changes at the Pdx-1 promoter in UPI islets. In control islets, the Pdx1 promoter is normally found in an unmethylated (open circles) open chromatin state allowing access to transcription factors like USF-1 and associated with nucleosomes characterized by acetylated histones H3 and H4 (H3Ac, H4Ac; gray triangles) and with the H3K4me3 (white hexagons). In islets collected form offspring exposed to UPI, histone acetylation is lost through association with a mSin3A-HDAC1-DNMT1 repressor complex. The activating histone modification H3K4me3 disappears while the silencing histone modification H3K9me2 (black diamonds) accumulates. The UPI exposed chromatin is more compressed and extensive DNA methylation (black circles) locks in the transcriptionally silent state of Pdx-1 in the UPI islets.