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

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 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.

Epigenetics: The missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes

“…21 During fetal development there is rapid growth, cell replication, and differentiation and functional maturation of organs, as well as dynamic changes in epigenetic programming, including genome-wide erasures and re-establishment of chromatin marks. 79 Nutritional perturbations during Reductions in menin led to reductions in promoter occupancy at these genes and a subsequent increase in cell proliferation, providing a plausible mechanism for pregnancy-induced changes in islet expansion. Infusion of prolactin, a pregnancy hormone, downregulated Men1 expression and enhanced proliferation of β-cells.…”

Endocrine Disruptors and Fetal Programming

“…These processes are very sensitive to changes in the intrauterine environment [13]. Epidemiological studies and animals models support the concept that there is a critical period of developmental programming in which exposures to adverse intrauterine environments or neonatal events may make an individual more susceptible to the development of adult illnesses such as obesity and DM [14] [15].…”

“…GDM may thus result in both macrosomic offspring and intrauterine growth restriction [13] [24], depending on the degree of hyperglycemia presented [15] [21]. There is growing epidemiological evidence that excesso nutritional intake to the fetus can produce phenotypes similar to those of malnutrition in offspring [8].…”

“…The expression of maternal genes may alter the fetal environment, but the maternal intrauterine environment might, influence and modify fetal genetic expression and influence birth weight [13]. Many studies have shown that intrauterine growth restriction (IUGR) is associated with increased oxidative stress in human fetuses, because the limited availability of nutrients results in a change in redox status in susceptible fetal tissues leading to oxidative stress [13].…”

“…Many studies have shown that intrauterine growth restriction (IUGR) is associated with increased oxidative stress in human fetuses, because the limited availability of nutrients results in a change in redox status in susceptible fetal tissues leading to oxidative stress [13]. In the IUGR, low levels of oxygen are observed, showing a decrease in the activity of complexes of the electron transport chain, which will increase the levels of reactive oxygen species (ROS), which in turn initiate several oxidative reactions that will cause lesions, not only in the mitochondria but also in the cellular proteins, lipids and nucleic acids [13]. Nevertheless, it is important to mention that it will be a conceptual mistake to affirm that low birth weight alone can cause disease at a later stage in the life of the subject [10].…”