Hundal Ripudaman S, Petersen Kitt F, Mayerson Adam B, Randhawa Pritpal S, Inzucchi Silvio, Shoelson Steven E, Shulman Gerald I
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
J Clin Invest. 2002 May;109(10):1321-6. doi: 10.1172/JCI14955.
Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKbeta, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKbeta activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin ( approximately 7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-(2)H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a approximately 25% reduction in fasting plasma glucose, associated with a approximately 15% reduction in total cholesterol and C-reactive protein, a approximately 50% reduction in triglycerides, and a approximately 30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by approximately 20% and approximately 50%, respectively. Aspirin treatment also resulted in a approximately 20% reduction in basal rates of hepatic glucose production and a approximately 20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKbeta represents a new target for treating type 2 diabetes mellitus.
近期研究表明，丝氨酸激酶IKKβ的脂肪酸依赖性激活在胰岛素抵抗的发病机制中发挥关键作用，而IKKβ在组织炎症中起重要作用。最近有研究显示，高剂量水杨酸盐可抑制IKKβ活性，因此可能改善2型糖尿病患者的胰岛素抵抗并提高葡萄糖耐量。为验证这一假设，我们对9名2型糖尿病受试者进行了为期2周的阿司匹林（约7 g/d）治疗，并在治疗前后进行了研究。受试者接受了混合餐耐量试验和使用[6,6-(2)H2]葡萄糖的高胰岛素-正常血糖钳夹试验，以评估治疗前后的葡萄糖代谢情况。高剂量阿司匹林治疗使空腹血糖水平降低了约25%，同时总胆固醇和C反应蛋白降低了约15%，甘油三酯降低了约50%，胰岛素清除率降低了约30%，尽管体重没有变化。在混合餐耐量试验中，血浆葡萄糖和脂肪酸水平的曲线下面积分别下降了约20%和约50%。阿司匹林治疗还使肝脏葡萄糖生成的基础速率降低了约20%，并在钳夹期间匹配血浆胰岛素浓度的情况下，使胰岛素刺激的外周葡萄糖摄取提高了约20%。总之，这些数据支持了IKKβ是治疗2型糖尿病的新靶点这一假设。
