Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.

Abstract NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. It is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage. However, we show here that in contrast to canonical NRF2 activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. Using a combination of wild type, Nrf2-/-, p62-/-, or Nrf2-/-;p62-/- mice and an arsenic-induced diabetes model, we demonstrate that NRF2 and p62 are essential for promoting insulin resistance and glucose intolerance. Integrated transcriptomic and metabolomic analyses reveal a p62-and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis through the upregulation of four novel NRF2 target genes. In conclusion, our findings reveal a key pro-diabetic role for non-canonical NRF2 activation.