ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes
ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes
复制标题
DOI：
10.1016/j.bbrc.2016.05.087
复制
发表时间：
2016-08-05
影响因子：
3.1
通讯作者：
Shi, Dongyun
中科院分区：
文献类型：
--
作者：
Dong, Kelei;Ni, Hua;Shi, Dongyun
已知氧化应激导致糖尿病胰岛素抵抗，但其机制尚不清楚。本研究表明，活性氧（ROS）可通过上调戊糖途径，重新编程葡萄糖代谢，从而诱导2型糖尿病（T2 DM）的胰岛素抵抗。通过链脲佐菌素-高脂饮食（STZ-HFD）诱导的2型糖尿病大鼠模型，我们发现糖尿病大鼠表现出高水平的氧化应激并伴有胰岛素抵抗。缺氧诱导因子（HIF-1 α）蛋白表达及其下游靶点葡萄糖激酶（GK）上调;糖原合成相应增加;但糖酵解受到抑制，表现为磷酸果糖激酶-1（PFK-1）、丙酮酸激酶（PK）、磷酸-PFK-2/PFK-2（p-PFK-2/PFK-2）比率、乳酸脱氢酶（LDH）和丙酮酸脱氢酶激酶（PDK）;促进丙酮酸生成乙酰辅酶A的丙酮酸脱氢酶（PDH）也下降。而磷酸乙酰辅酶A羧化酶/乙酰辅酶A羧化酶（p-ACC/ACC）比值增加，意味着脂质β-氧化增加。戊糖途径被激活，如G6 PD活性和NADPH水平增加所示。结果提示，糖尿病大鼠通过增加戊糖途径来对抗ROS应激，并将糖酵解能量代谢途径重编程为脂质氧化，以补偿机体对ATP的需求，从而导致胰岛素抵抗。(C)2016 Elsevier Inc. All rights reserved.
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.