title: The Keap1-Nrf2 system prevents onset of diabetes mellitus.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Yuki
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Negishi
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis; D007328:Insulin / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D003598:Cytoskeletal Proteins; D007328:Insulin; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2