title: Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice.
abstract: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces a battery of cytoprotective genes after oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared with wild-type mice, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an intraperitoneal glucose challenge. In the present study, blood glucose, serum insulin, urine flow rate, and hepatic expression of glucose-related genes were quantified in male diabetic wild-type and Nrf2-null mice. Type 1 diabetes was induced with a single intraperitoneal dose (200 mg/kg) of streptozotocin (STZ). Histopathology and serum insulin levels confirmed depleted pancreatic beta-cells in STZ-treated mice of both genotypes. Five days after STZ, Nrf2-null mice had higher blood glucose levels than wild-type mice. Nine days after STZ, polyuria occurred in both genotypes with more urine output from Nrf2-null mice (11-fold) than wild-type mice (7-fold). Moreover, STZ-treated Nrf2-null mice had higher levels of serum beta-hydroxybutyrate, triglycerides, and fatty acids 10 days after STZ compared with wild-type mice. STZ reduced hepatic glycogen in both genotypes, with less observed in Nrf2-null mice. Increased urine output and blood glucose in STZ-treated Nrf2-null mice corresponded with enhanced gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase)- and reduced glycolysis (pyruvate kinase)-related mRNA expression in their livers. Furthermore, the Nrf2 activator oltipraz lowered blood glucose in wild-type but not Nrf2-null mice administered STZ. Collectively, these data indicate that the absence of Nrf2 worsens hyperglycemia in type I diabetic mice and Nrf2 may represent a therapeutic target for reducing circulating glucose levels.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reisman
authors.forename: Ronnie L
authors.initials: RL
authors.lastname: Yeager
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018149:Glucose Intolerance / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics; D006943:Hyperglycemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013871:Thiones; D013876:Thiophenes; D014563:Urodynamics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008112:Liver Glycogen; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)