title: Dietary nitrite improves insulin signaling through GLUT4 translocation.
abstract: Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes.
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Torregrossa
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Potts
authors.affiliation: California State University at Fullerton, Fullerton, CA 92831, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Pierini
authors.affiliation: The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Mayank
authors.initials: M
authors.lastname: Aranke
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA.
authors.forename: Harsha K
authors.initials: HK
authors.lastname: Garg
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas at Houston, Houston, TX 77030, USA. Electronic address: Nathan.Bryan@uth.tmc.edu.
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005033:Ethylmaleimide / Q000494:pharmacology; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012977:Sodium Nitrite / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051275:Glucose Transporter Type 4; D016271:Proto-Oncogene Proteins c-myc; C495693:Slc2a4 protein, mouse; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011972:Receptor, Insulin; D012977:Sodium Nitrite; D005033:Ethylmaleimide
keywords: Cell signaling; Diabetes; Free radicals; GLUT4; Insulin; Nitric oxide; Nutrition