title: Cortisol promotes endoplasmic glucose production via pyridine nucleotide redox.
abstract: Both increased adrenal and peripheral cortisol production, the latter governed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to the maintenance of fasting blood glucose. In the endoplasmic reticulum (ER), the pyridine nucleotide redox state (NADP/NADPH) is dictated by the concentration of glucose-6-phosphate (G6P) and the coordinated activities of two enzymes, hexose-6-phosphate dehydrogenase (H6PDH) and 11β-HSD1. However, luminal G6P may similarly serve as a substrate for hepatic glucose-6-phophatase (G6Pase). A tacit belief is that the G6P pool in the ER is equally accessible to both H6PDH and G6Pase. Based on our inhibition studies and kinetic analysis in isolated rat liver microsomes, these two aforesaid luminal enzymes do share the G6P pool in the ER, but not equally. Based on the kinetic modeling of G6P flux, the ER transporter for G6P (T1) preferentially delivers this substrate to G6Pase; hence, the luminal enzymes do not share G6P equally. Moreover, cortisol, acting through 11β-HSD1, begets a more reduced pyridine redox ratio. By altering this luminal redox ratio, G6P flux through H6PDH is restrained, allowing more G6P for the competing enzyme G6Pase. And, at low G6P concentrations in the ER lumen, which occur during fasting, this acute cortisol-induced redox adjustment promotes glucose production. This reproducible cortisol-driven mechanism has been heretofore unrecognized.
authors: Department of PediatricsShandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, PR China Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Zengmin
authors: Z
authors: Wang
authors: Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Gail J
authors: GJ
authors: Mick
authors: Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA Department of EndocrinologyChildren's Hospital of Soochow University, Suzhou, Jiangsu, PR China.
authors: Rongrong
authors: R
authors: Xie
authors: Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Xudong
authors: X
authors: Wang
authors: Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Xuemei
authors: X
authors: Xie
authors: Department of PediatricsShandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, PR China kmccormick@peds.uab.edu gmlipeds@gmail.com.
authors: Guimei
authors: G
authors: Li
authors: Division of Pediatric EndocrinologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA kmccormick@peds.uab.edu gmlipeds@gmail.com.
authors: Kenneth L
authors: KL
authors: McCormick
mesh_terms: D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006854:Hydrocortisone / Q000502:physiology*; D008862:Microsomes, Liver; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D014638:Vanadates
chemical_list: D002245:Carbon Dioxide; D014638:Vanadates; D009249:NADP; D019298:Glucose-6-Phosphate; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D005947:Glucose; D006854:Hydrocortisone
keywords: cortisol; glucose; pyridine nucleotides; rat liver microsomes