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

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Abstract

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.

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Abbreviations

IUGR:

intrauterine growth retardation

SGA:

small for gestational age

LP:

low protein

HDAC1:

histone deacetylase 1

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Acknowledgements

Dr. Rebecca Simmons is supported by the National Institutes of Health grant nos. DK55704 and AG20898.

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  1. Department of Pediatrics, Children’s Hospital Philadelphia and University of Pennsylvania School of Medicine, BRB II/III, Rm 1308, 421 Curie Blvd, Philadelphia, PA, 19104, USA

    Rebecca A. Simmons

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Simmons, R.A. Role of metabolic programming in the pathogenesis of β-cell failure in postnatal life. Rev Endocr Metab Disord 8, 95–104 (2007). https://doi.org/10.1007/s11154-007-9045-1

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