Role of metabolic programming in the pathogenesis of beta-cell failure in postnatal life.
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 beta-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 beta-cell proliferation leads to a progressive decline in beta-cell mass. Using this model, we have tested the hypothesis that uteroplacental insufficiency disrupts the function of the electron transport chain in the fetal beta-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 beta-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 beta-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.
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. rsimmons@mail.med.upenn.edu
Rebecca A
RA
Simmons
D000328:Adult; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species