Figure 7.

Nrf2 increases β-cell mass by increasing survival and promoting β-cell proliferation. Glucose metabolism generates ROS in β-cells, which changes Keap1 conformation, decreases Nrf2:Keap1 interaction and proteolytic degradation, and increases Nrf2 abundance and transcriptional activity. CDDO-Me also activates Nrf2 by inhibiting Keap1. Nrf2 target genes include antioxidant enzymes and enzymes that produce NADPH, which is used by antioxidant enzymes to protect β-cells from ROS and as reducing equivalents for synthesis of RNA, DNA, and membrane in proliferating cells. Activation of Nrf2 is also associated with increased expression of cell-cycle regulators (mainly cyclin D1) and increased insulin content. Thus, the combined actions of Nrf2, protection from apoptosis, and increased proliferation lead to increased β-cell mass. Ub, ubiquitin. Reprinted with permission from J. Gregory (Mount Sinai Health System).