Mechanisms by Which IUGR Leads to Diabetes

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PROJECT SUMMARY Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is linked to the later development of type 2 diabetes (T2D). We have developed an experimental animal model of IUGR caused by uteroplacental insufficiency that affects the development of the fetus by permanently altering susceptible cells, such as ß-cells, and leads to the development of T2D in adulthood. Our preliminary data suggest that the mechanism by which IUGR leads to the development of T2D in adulthood is via a transient activation of the Th2 response in fetal islets resulting in localized inflammation. This is associated with the production of high levels of IL-4 and IL-10 in fetal islets. Although this immune response is short- lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. However, it is not known which immune cells or T cell subtypes contribute to the production of these Th2 cytokines. As each of these immune cell types have a particular role in immune regulation, it is critically important to determine the phenotypic profile of T cell subsets. Surprisingly, blocking the action of a single Th2 cytokine, IL-4, restores vascularity and ß-cell function permanently in IUGR adult animals. This suggests that IL-4 orchestrates a cascade of events leading to the abnormal ß-cell phenotype in the IUGR animal. Epigenetic mechanisms regulate Th2 cell activation both in the fetus and adult. The Th2 cytokine locus is highly conserved and demethylated in resting normal fetal and neonatal CD4+ cells. Thus, additional epigenetic mechanisms must underlie the exaggerated Th2 effector function in IUGR cells. These findings lead us to hypothesize that IUGR induced expansion of Th2-type effector cells including macrophages and eosinophils occurs via epigenetic mechanisms resulting in permanent ß-cell dysfunction. We propose the following aims: Specific Aim 1: To determine whether fetal IUGR immune cells are functionally distinct from controls resulting in an amplified Th2 response. Specific Aim 2: To define the epigenetic landscape in IUGR fetal and neonatal immune cells. Specific Aim 3: Determine the mechanisms by which IL4 production causes ß-cell dysfunction in IUGR animals. Through the comprehensive analyses in the in vivo model, the results of the proposed project will build a solid standard for extrapolation of effects and mode of action to other types of inflammatory processes that may be identified as potential inducers of obesity and related metabolic diseases later in life.