Sunday, April 2, 2023
4/2/2023
Summary The late stages of the mammalian pregnancy are accompanied with increased insulin resistance due to the increased glucose demand of the growing fetus. Therefore, as a compensatory response, in order to maintain the maternal normal blood glucose levels, the beta cells mass expands leading to increased insulin release. Beta cell proliferation, beta cell neogenesis, and decreased beta cell apoptosis, are believed to be major contributors for beta cell adaptive response during pregnancy and defects in this adaptive response can lead to gestational diabetes mellitus (GDM). My preliminary results indicate that Nrf2 is required for adaptive beta cell expansion in adult mice during overnutrition, and that Nrf2 levels are upregulated in beta cells of pregnant mice. Despite multiple studies describing Nrf2 protective effects on beta cells in Type 2 and Type 1 diabetic models, no study has ever uncovered the role of Nrf2 in the expansion of beta cell mass during pregnancy. Does in vivo loss- or gain-of-Nrf2 function affect beta cell proliferation, survival and mass in pregnant mice? Does this potential alteration persist in the early post-partum period? Does in vivo loss- or gain-of-Nrf2 function affect insulin secretion in pregnant mice? Does in vivo loss- or gain-of-Nrf2 function affect glucose homeostasis in pregnant mice? Which genes are upregulated and downregulated in islets during pregnancy in response to in vivo loss or gain of Nrf2 function? Which are the Nrf2 target genes in islets during pregnancy? Do human beta cells also require Nrf2 for pregnancy-driven proliferation? These important questions about the physiological role of Nrf2 in beta cells during pregnancy need to be answered to advance our knowledge and find therapeutic means to treat GDM. We hypothesize that Nrf2 is necessary for beta cell expansion during pregnancy and that disruption of Nrf2 expression or function leads to GDM. We believe Nrf2 can serve as a potential therapeutic target for treating GDM. We will test our hypothesis by completing the following specific aims: 1) To determine the role of Nrf2 on the expansion of beta-cell mass during pregnancy. 2) To uncover the mechanisms by which Nrf2 regulates beta-cell mass expansion during pregnancy. 3) To test if Nrf2 is necessary for pregnancy-mediated adaptive human beta cell proliferation in vivo. These studies will provide insight into how Nrf2 promotes expansion of functional beta-cell mass during pregnancy and will provide a crucial basic platform for designing and testing novel therapeutic strategies for the treatment of GDM.
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