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HNF4A and Diabetes

Injury Before Insult?

From the Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Corresponding author: Ben Z. Stanger, Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: bstanger@mail.med.upenn.edu

Abbreviations: MODY, maturity-onset diabetes of the young

The first 20% of the full text of this article appears below.

One of the distinguishing features of vertebrate development is its highly regulative nature. Following developmental perturbations, vertebrate embryos exhibit a robust ability to compensate and normalize structure. However, such appearances may be deceiving, as it has become clear that relatively mild perturbations in embryonic growth can result in profound metabolic disorders—including diabetes—decades later. This association has important clinical implications, but a complete understanding of the cellular and molecular relationship between embryonic development and adult physiology has been slow to emerge.

The first compelling evidence that intrauterine environment dictates later metabolic outcome was the cohort study of Ravelli et al. (1) of 300,000 men conceived during the Dutch famine of 1944–1945. Embryos exposed to malnutrition during the first half of pregnancy, but not later, had significantly higher rates of obesity at age 19 years, indicating that a nutrient-deprived environment early in development has long-lasting metabolic consequences (1). Human and animal studies have subsequently confirmed a relationship between embryonic environment, particularly intrauterine growth retardation, and later occurrence of type 2 diabetes (rev. in 2,3). Although it was initially postulated that hypothalamic-mediated changes in appetite might underlie adult metabolic derangements, low–birth weight infants were found to also have reduced pancreatic β-cell mass . . . [Full Text of this Article]

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