title: ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes.
abstract: 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-1α) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Kelei
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Ni
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Michael
authors.initials: M
authors.lastname: Halim
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China. Electronic address: dyshi@fudan.edu.cn.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Shi
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D017382:Reactive Oxygen Species; D009249:NADP; D005947:Glucose
keywords: Glycolysis; Insulin resistance; Pentose pathway; Reactive oxidative stress; Type 2 diabetes mellitus