The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance, likely due to enhanced glucose demand for the growing fetus. Therefore, as an adaptive process to maintain normal blood glucose levels during pregnancy, maternal insulin–producing cell (β–cell) mass expands, leading to increased insulin release. Defects in functional β–cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate functional β–cell mass expansion and with a systematic increase in oxidative stress (OS).
We recently showed that the levels of NRF2, the master regulator of OS, are upregulated in mouse β–cells at gestational day 15 (Haidery et al. Redox Biology 2025). Moreover, towards the end of pregnancy, mice with β–cell–specific Nrf2 deletion (βNrf2KO) display reduced β–cell proliferation, increased β–cell OS and 4–HNE (4–Hydroxy–2–Nonenal, a lipid peroxidation product formed under OS) levels, compromised β–cell function, and elevated β–cell death, leading to impaired β–cell mass expansion and dysregulated glucose homeostasis. Importantly, the gestational hormone 17–β–estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2–induced protection of β–cells against OS, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in β–cells. Collectively, these data highlight the critical role of NRF2 in regulating OS during the adaptive response of β–cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.
We propose further investigating NRF2 regulation in β–cells during human pregnancy. Specifically, we aim to determine whether, as observed in rodents, NRF2 levels and activity are upregulated in human β–cells during normal pregnancy and whether they are impaired in GDM. To test this, we plan to immunolabel pancreatic tissues from pregnant (donors with normal pregnancy and GDM) and non–pregnant women using antibodies against (a) C–peptide and NRF2; (b) C–peptide and Sod1 (a Nrf2 target gene); (c) C–peptide and Nqo1 (another Nrf2 target gene); and (d) C–peptide and 4–HNE. NRF2 levels and activity, as well as OS marker (4–HNE) will be quantitated in β–cells.
In summary, we aim to explore how NRF2, a key factor that protects cells from oxidative stress, supports insulin–producing cells during pregnancy and whether its failure may play a role in gestational diabetes.
