Nrf2 and the expansion and preservation of beta cell mass

Summary All major forms of diabetes result from a deficit of functional β-cells. Thus, it is critically important to develop therapies to preserve and expand β-cell mass. We have demonstrated that Nrf2, the master transcriptional regulator of antioxidant enzymes, plays a significant role in modulating β-cell mass. Nrf2 protects -cells from oxidative stress, but the mechanisms, external cues, and signaling pathways that regulate Nrf2 are incompletely understood. We recently found that Nrf2 activation expands cell mass, preserves -cell identity and insulin content, and improves glucose tolerance after a high caloric diet. Treatments that increase cAMP through G protein-coupled receptors (GPCRs; for example, agonism of Gs-linked EP4 prostaglandin E2 (PGE2) receptors or the GLP-1 receptor (GLP-1R), or antagonism of Gi-linked EP3 PGE2 receptors), also lead to increased β-cell proliferation, retention of β-cell identity and protection of β-cell mass after challenge with cytokines or glucose toxicity. Importantly for this proposal, our published and preliminary data suggest that Nrf2 is activated by and necessary for the effects of PGE2 receptor modulation and for the effects mediated by GLP-1 receptor agonists. In this proposal our assembled team is uniquely positioned to explore the relationship between Nrf2 activation and other pathways known to protect β-cells from oxidative stress, retain β-cell identity, and promote adaptive β-cell expansion. We hypothesize that the Nrf2 pathway is a common junction between eicosanoid and incretin signaling and thus is a critical nexus of β-cell preservation, identity, adaptation, and function; therefore, Nrf2 is crucial for these agents to improve functional β-cell mass in diabetes. Specific Aim 1 will test the hypothesis that activation of Nrf2 and EP3 antagonism and/or GLP-1R or EP4 agonism work together to enhance β-cell proliferation and β-cell protection from oxidative stress. Specific Aim 2 Identify β-cell-specific Nrf2 targets and characterize the transcriptome and chromatin landscape of Nrf2 activation, EP3 antagonism, and/or GLP-1R or EP4 agonism as these treatments preserve β-cell mass. Specific Aim 3 Explore the in vivo therapeutic potential of combined Nrf2 activation with EP receptor modulation and/or GLP-1R agonism. These studies will provide key mechanistic information, identify new β-cell-specific gene targets, and test the therapeutic potential of three attractive and inter-related pathways that will be of great value to the field for the therapeutic preservation and expansion of functional β-cell mass highly needed in diabetes.