TY - JOUR T1 - Nrf2 deletion impairs glucose tolerance and exacerbates hyperglycemia in Type 1 diabetic mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.162271 SP - jpet.109.162271 AU - Lauren M. Aleksunes AU - Scott A. Reisman AU - Ronnie L. Yeager AU - Michael J. Goedken AU - Curtis D. Klaassen Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/01/19/jpet.109.162271.abstract N2 - The transcription factor Nrf2 induces a battery of cytoprotective genes following oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared to wild-types, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an ip 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 ip 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-types. Nine days after STZ, polyuria occurred in both genotypes with more urine output from Nrf2-null mice (11-fold) than wild-types (7-fold). Moreover, STZ-treated Nrf2-null mice had higher levels of serum beta-hydroxybutyrate, triglycerides, and fatty acids 10 days after STZ compared to wild-types. 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. Lastly, 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 that Nrf2 may represent a therapeutic target for reducing circulating glucose levels.The American Society for Pharmacology and Experimental Therapeutics ER -