Role of metabolic programming in the pathogenesis of β-cell failure in postnatal life


DOI: 10.1007/s11154-007-9045-1

Cite this article as:
Simmons, R.A. Rev Endocr Metab Disord (2007) 8: 95. doi:10.1007/s11154-007-9045-1


Intrauterine growth retardation (IUGR) has been linked to later development of type 2 diabetes in adulthood. Human studies indicate that individuals who were growth retarded at birth have impaired insulin secretion and insulin resistance. Multiple animal models of IUGR demonstrate impaired β-cell function and development. We have developed a model of IUGR in the rat that leads to diabetes in adulthood with the salient features of most forms of type 2 diabetes in the human: progressive defects in insulin secretion and insulin action prior to the onset of overt hyperglycemia. Decreased β-cell proliferation leads to a progressive decline in β-cell mass. Using this model, we have tested the hypothesis that uteroplacental insufficiency disrupts the function of the electron transport chain in the fetal β-cell and leads to a debilitating cascade of events: increased production of reactive oxygen species, which in turn damage mitochondrial (mt) mtDNA and causes further production of reactive oxygen species (ROS). The net result is progressive loss of β-cell function and eventual development of type 2 diabetes in the adult. Studies in the IUGR rat also demonstrate that an abnormal intrauterine environment induces epigenetic modifications of key genes regulating β-cell development; experiments directly link chromatin remodeling with suppression of transcription. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring.


Intrauterine growth retardation Type 2 diabetes Fetal origins of adult disease Epigenetics Mitochondria Oxidative stress 



intrauterine growth retardation


small for gestational age


low protein


histone deacetylase 1

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of PediatricsChildren’s Hospital Philadelphia and University of Pennsylvania School of MedicinePhiladelphiaUSA

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