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.
Simmons
Rebecca A
RA
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
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