FCM-UNICAMP, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo 13083-887, Brazil.
Diabetologia. 2009 Nov;52(11):2425-34. doi: 10.1007/s00125-009-1498-1.
AIM/HYPOTHESIS: High-dose aspirin treatment improves fasting and postprandial hyperglycaemia in patients with type 2 diabetes, as well as in animal models of insulin resistance associated with obesity and sepsis. In this study, we investigated the effects of aspirin treatment on inducible nitric oxide synthase (iNOS)-mediated insulin resistance and on S-nitrosylation of insulin receptor (IR)-beta, IRS-1 and protein kinase B (Akt) in the muscle of diet-induced obese rats and also in iNos (also known as Nos2)-/- mice on high fat diet.
Aspirin (120 mg kg-1 day-1 for 2 days) or iNOS inhibitor (L-NIL; 80 mg/kg body weight) were administered to diet-induced obese rats or mice and iNOS production and insulin signalling were investigated. S-nitrosylation of IRbeta/IRS-1 and Akt was investigated using the biotin switch method.
iNOS protein levels increased in the muscle of diet-induced obese rats, associated with an increase in S-nitrosylation of IRbeta, IRS-1 and Akt. These alterations were reversed by aspirin treatment, in parallel with an improvement in insulin signalling and sensitivity, as measured by insulin tolerance test and glucose clamp. Conversely, while aspirin reversed the increased phosphorylation of IkappaB kinase beta and c-Jun amino-terminal kinase, as well as IRS-1 serine phosphorylation in diet-induced obese rats and iNos -/- mice on high-fat diet, these alterations were not associated with the improvement of insulin action induced by this drug.
CONCLUSIONS/INTERPRETATION: Our data demonstrate that aspirin treatment not only reduces iNOS protein levels, but also S-nitrosylation of IRbeta, IRS-1 and Akt. These changes are associated with improved insulin resistance and signalling, suggesting a novel mechanism of insulin sensitisation evoked by aspirin treatment.
目的/假设：大剂量阿司匹林治疗可改善 2 型糖尿病患者的空腹和餐后高血糖，以及与肥胖和脓毒症相关的胰岛素抵抗的动物模型。在这项研究中，我们研究了阿司匹林治疗对诱导型一氧化氮合酶（iNOS）介导的胰岛素抵抗以及对饮食诱导肥胖大鼠肌肉中胰岛素受体（IR）-β、胰岛素受体底物 1（IRS-1）和蛋白激酶 B（Akt）的 S-亚硝基化的影响，还研究了高脂肪饮食中 iNos（也称为 Nos2）-/-小鼠。
给饮食诱导肥胖的大鼠或小鼠给予阿司匹林（120mg/kg/天，2 天）或 iNOS 抑制剂（L-NIL；80mg/kg 体重），并研究 iNOS 产生和胰岛素信号。使用生物素转换法研究 IRβ/IRS-1 和 Akt 的 S-亚硝基化。
饮食诱导肥胖大鼠肌肉中的 iNOS 蛋白水平增加，与 IRβ、IRS-1 和 Akt 的 S-亚硝基化增加有关。这些改变通过阿司匹林治疗得到逆转，与胰岛素信号和敏感性的改善平行，如胰岛素耐量试验和葡萄糖钳夹所示。相反，虽然阿司匹林逆转了饮食诱导肥胖大鼠和高脂肪饮食中 iNos -/-小鼠的 IkappaB 激酶β和 c-Jun 氨基末端激酶磷酸化以及 IRS-1 丝氨酸磷酸化的增加，但这些改变与该药物引起的胰岛素作用改善无关。
结论/解释：我们的数据表明，阿司匹林治疗不仅降低了 iNOS 蛋白水平，而且降低了 IRβ、IRS-1 和 Akt 的 S-亚硝基化。这些变化与胰岛素抵抗和信号的改善有关，提示阿司匹林治疗引起的胰岛素敏化的新机制。
