The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Akira Uruno, Yuki Furusawa, Yoko Yagishita, Toshiaki Fukutomi, Hiroyuki Muramatsu, Takaaki Negishi, Akira Sugawara, Thomas W. Kensler, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

183 Scopus citations


Transcription factor Nrf2(NF-E2-related factor 2)regulates a broad cytoprotective response to environmental stresses. Keap1(Kelch-like ECH-associated protein 1)is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown(Keap1flox/-)markedly suppresses the onset of diabetes. When Keap1flox/-mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1flox/-also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im{oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)2996-3010
Number of pages15
JournalMolecular and cellular biology
Issue number15
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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