[R01] Pancreatic Beta-Cells, Oxidative Stress, and Gestational Diabetes
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2031-05-31
Importo max: 776.570 EUR
Paese: US
Descrizione
Project Summary
Gestational diabetes mellitus (GDM), a metabolic condition of glucose intolerance with onset or first recognition
during pregnancy, affects approximately 7.6% of all pregnancies in the U.S. GDM increases the risk of
developing Type 2 Diabetes (T2D) post-pregnancy in the mother and promotes fetal developmental disorders.
While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate
adaptive expansion of pancreatic islet insulin secreting cells (β-cells) and increased systemic oxidative stress.
Oxidative stress occurs when the amount of intracellular reactive oxygen species (ROS) exceeds the cell ability to
detoxify it via its antioxidant defense systems. One of the consequences of high ROS levels is the generation of
an oxidative protein post-translational modification called protein carbonylation (PC). PC can impair protein’s
function and stability and is associated with many human diseases, including diabetes. Yet, the effect of oxidative
stress and PC on β-cells during pregnancy is understudied. NRF2 is the master regulator of cellular antioxidant
defense and mutations in NRF2 gene are associated with T2D. We have previously shown that NRF2 is
essential for the adaptive expansion of β-cells in obesity and for normal β-cell growth at early stages of life.
Our preliminary data shows that human β-cell NRF2 levels are increased in islets from pregnant donors but
not in islets from GDM donors. Our recently published data show that NRF2 levels are also increased in
rodent β-cells during pregnancy and that deletion of Nrf2 in mouse β-cells significantly increases β-cells’
oxidative stress, enhances β-cell death, compromises β-cell function, blunts adaptive expansion of β-cell mass,
and dysregulates glucose homeostasis, which are all characteristics of GDM. Additionally, Nrf2 deletion in β-
cells reduces the expression of enzymes that inhibit formation of PC. Importantly, the steroid hormone
17β-estradiol (E2) which has antioxidative properties increases NRF2 levels in rodent β-cells. We therefore
hypothesize that E2 signaling, through estrogen receptor α (ERα), regulates NRF2 in β-cells to
preserve functional β-cell mass during pregnancy by reducing PC, thereby preventing GDM. To test this
hypothesis, we have developed the following specific aims: (1) Examine how E2/ERα regulates NRF2 and
the redox balance in β-cells during pregnancy; (2) Determine the effect of ERα/NRF2 on islet PC during
pregnancy; and to (3) Determine the effects of NRF2 in the human β-cell during pregnancy. Successful
completion of these aims will provide further understanding of the mechanisms that lead to GDM and will be
the basis for future GDM therapeutics.
Istituzione: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
PI: Sharon Alterzon
Progetto: 1R01DK145729-01A1
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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