Jiang Hong, Torregrossa Ashley C, Potts Amy, Pierini Dan, Aranke Mayank, Garg Harsha K, Bryan Nathan S
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Health Science Center, Houston, TX 77030, USA.
California State University at Fullerton, Fullerton, CA 92831, USA.
Free Radic Biol Med. 2014 Feb;67:51-7. doi: 10.1016/j.freeradbiomed.2013.10.809. Epub 2013 Oct 21.
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.
2型糖尿病是一种代谢紊乱综合征，由于胰岛素生物有效性降低导致血糖异常升高。2型糖尿病与一氧化氮（NO）途径受损有关，该途径可能是代谢紊乱与心血管疾病之间的关键联系。胰岛素介导的葡萄糖转运蛋白4（GLUT4）转位涉及磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/Akt）信号级联反应，该反应导致内皮型一氧化氮合酶（eNOS）激活。在糖尿病期间，eNOS功能失调。我们推测，eNOS衍生的NO缺失会终止信号级联反应，因此无法激活GLUT4转位，而膳食亚硝酸盐可能修复这一途径。在本研究中，我们给db/db糖尿病小鼠施用50mg/L亚硝酸钠，持续4周。治疗4周后，db/db小鼠体重增加减少，空腹血糖水平改善，胰岛素水平降低。使用稳定表达胰岛素受体和myc-GLUT4eGFP蛋白的CHO-HIRc-myc-GLUT4eGFP细胞系以及稳定表达带有Myc表位的大鼠GLUT4的L6骨骼肌细胞（L6-GLUT4myc）进行的细胞培养实验表明，NO、亚硝酸盐和GSNO可独立于胰岛素刺激GLUT4转位，而N-乙基马来酰亚胺（NEM）可抑制这种转位。我们的数据共同表明，亚硝酸盐通过恢复GLUT4信号转位的NO依赖性亚硝化作用来改善胰岛素信号。这些数据表明，亚硝酸盐或其他亚硝化剂对GLUT4进行的NO介导的亚硝化作用对于靶组织中的GLUT4转位是必要且充分的。对该途径的描述可能证明高硝酸盐/亚硝酸盐饮食与血糖指数相结合可为糖尿病的管理和治疗提供一种安全且营养的方案。
