α-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats
α-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats
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DOI：
10.1055/s-2004-825760
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发表时间：
2004-08-01
影响因子：
2.2
通讯作者：
Al-Mulla, F
中科院分区：
文献类型：
--
作者：
Bitar, MS;Wahid, S;Al-Mulla, F
外周组织的葡萄糖摄取和代谢受损是I型和II型糖尿病的共同特征。在氧化应激和胰岛素信号通路内的早期事件的背景下，使用来自非肥胖、胰岛素抵抗的II型糖尿病Goto-Kakizaki（GK）大鼠（一种众所周知的人类II型糖尿病的遗传大鼠模型）的比目鱼肌来检查这种现象。GK大鼠比目鱼肌胰岛素刺激的葡萄糖转运受损。GK大鼠比目鱼肌中以葡萄糖氧化和糖原合成为代表的氧化和非氧化葡萄糖处置途径与其相应的对照值相比，似乎对胰岛素的作用具有抗性。这些糖尿病相关的葡萄糖处理异常与胰岛素介导的蛋白激酶B（Akt/PK B）和胰岛素受体底物-1（IRS-1）相关的磷脂酰肌醇3-激酶（PI 3-激酶）活性增强显著减少有关;这两种激酶是胰岛素信号通路中的关键元件。此外，GK糖尿病大鼠比目鱼肌中的氧化应激状态升高，如蛋白质结合羰基含量所示。长期给予疏水性/亲水性抗氧化剂α-硫辛酸（ALA，100 mg/kg，ip）部分改善了糖尿病相关的葡萄糖代谢缺陷、蛋白质氧化以及胰岛素对胰岛素信号传导途径各个步骤的激活，包括酶Akt/PKB和PI-3激酶。总的来说，目前的研究阐明了氧化应激可能确实参与某些类型的胰岛素抵抗的发病机制。它也与包括有效的抗氧化剂，如ALA在抗糖尿病治疗的医疗设备的概念相一致。
Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetesrelated abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha-lipoic-acid (ALA, 100 mg/kg, ip) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.