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

NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2−/−, p62−/−, or Nrf2−/−; p62−/− mice exposed to arsenic in the drinking water for 20 weeks. In contrast to canonical oxidative/electrophilic 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. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis. •The role of non-canonical activation of the Nrf2 signaling pathway in type II diabetes has not been determined.•Chronic activation of Nrf2 promotes a pro-diabetic shift in the liver polyol pathway that increases blood glucose levels.•Four newly identified Nrf2 target genes are responsible for the diabetogenic shift in liver carbohydrate metabolism.