Abstract
The link between an adverse intrauterine environment and the development of disease later in life has been observed in offspring of pregnancies complicated by obesity and diabetes, but the molecular mechanisms underlying this phenomenon are unknown. In this review, we highlight recent publications exploring the role of gestational diabetes mellitus in the programming of disease in the offspring. We also review recent publications aiming to identify mechanisms responsible for the “programming effect” that results from exposure to diabetes in utero. Finally, we highlight research on the role of epigenetic regulation of gene expression in an animal model of uteroplacental insufficiency where the offspring develop diabetes as a model by which an exposure to the mother can alter epigenetic modifications that affect expression of key genes and ultimately lead to the development of diabetes in the offspring.
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•• Pinney SE, Jaeckle Santos LJ, Han Y, Stoffers DA, Simmons RA. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia. 2011;54:2606–14. The abnormal intrauterine mileau of IUGR permanently alters gene expression and function of pancreatic β cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR islets, suggesting an epigenetic mechanism is responsible for the silencing. This study demonstrates a novel mechanism whereby a short treatment course of Ex-4 in the newborn period permanently increases HAT activity by recruiting USF1 and PCAF to the Pdx1 promoter. This restores chromatin structure at the Pdx1 promoter and prevents DNA methylation, thus preserving Pdx1 transcription in IUGR islets..
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Pinney, S.E., Simmons, R.A. Metabolic Programming, Epigenetics, and Gestational Diabetes Mellitus. Curr Diab Rep 12, 67–74 (2012). https://doi.org/10.1007/s11892-011-0248-1
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DOI: https://doi.org/10.1007/s11892-011-0248-1