ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes

被引：63
作者：
Dong, Kelei [1 ]
Ni, Hua [1 ]
Wu, Meiling [1 ]
Tang, Ziqing [1 ]
Halim, Michael [1 ]
Shi, Dongyun [1 ]
机构：
[1] Fudan Univ, Free Rad Regulat & Applicat Res Ctr, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200032, Peoples R China
来源：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2016年 / 476卷 / 04期
基金：
中国国家自然科学基金;
关键词：
Reactive oxidative stress; Insulin resistance; Pentose pathway; Glycolysis; Type 2 diabetes mellitus; OXIDATIVE STRESS; RAT; CELLS; MODEL; DIET;
D O I：
10.1016/j.bbrc.2016.05.087
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Oxidative stress is known to contribute to insulin resistance in diabetes, however the mechanism is not clear. Here we show that reactive oxygen species (ROS) could reprogram the glucose metabolism through upregulating the pentose pathway so as to induce insulin resistance in type 2 diabetes (T2DM). By using streptozotocin-high fat diet (STZ-HFD) induced T2DM in rats, we show that diabetic rats exhibited high level of oxidative stress accompanied with insulin resistance. Hypoxia inducible factor (HIF-1 alpha.) protein expression as well as its downstream target glucokinase (GK), were upregulated; The glycogen synthesis increased accordingly; However the glycolysis was inhibited as indicated by decreased phosphofructokinase-1 (PFK-1), pyruvate kinase (PK), phospho-PFK-2/PFK-2 (p-PFK-2/PFK-2) ratio, lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK); Pyruvate dehydrogenase (PDH) which promotes pyruvate to generate acetyl-CoA declined as well. While phospho-acetyl-CoA carboxylase/acetyl-CoA carboxylase (p-ACC/ACC) ratio increased, meaning that lipid beta-oxidation increased. The pentose pathway was activated as indicated by increased G6PD activity and NADPH level. Our results suggest that diabetic rats countervail ROS stress through increasing pentose pathway, and reprogram the energy metabolic pathway from glycolysis into lipid oxidation in order to compensate the ATP requirement of the body, which causes insulin resistance. (C) 2016 Elsevier Inc. All rights reserved.
引用
收藏
页码：204 / 211
页数：8
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