Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
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DOI：
10.1172/jci14955
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发表时间：
2002-05
期刊：
影响因子：
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通讯作者：
R. Hundal;K. Petersen;Adam Mayerson;P. Randhawa;S. Inzucchi;S. Shoelson;G. Shulman
中科院分区：
文献类型：
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作者：
R. Hundal;K. Petersen;Adam Mayerson;P. Randhawa;S. Inzucchi;S. Shoelson;G. Shulman
最近的研究表明，在组织炎症中起关键作用的丝氨酸激酶IKKbeta在胰岛素抵抗的发病机制中发挥着关键作用，这种激活依赖于脂肪酸。高剂量的水杨酸盐最近被证明可以抑制IKKβ活性，因此可能改善2型糖尿病患者的胰岛素抵抗和糖耐量。为了验证这一假设，我们研究了9名2型糖尿病患者服用阿司匹林(约7g/d)治疗2周前后的情况。受试者接受混合餐耐量试验和高胰岛素-正常血糖钳夹试验，评估治疗前后的葡萄糖周转情况。在体重没有变化的情况下，大剂量阿司匹林治疗导致空腹血糖下降约25%，总胆固醇和C反应蛋白下降约15%，甘油三酯下降约50%，胰岛素清除率下降约30%。在混合餐耐量测试中，血糖和脂肪酸水平曲线下的面积分别下降了约20%和约50%。阿司匹林治疗还导致肝脏葡萄糖产生的基础速率降低了约20%，在钳夹期间，在匹配的血浆胰岛素浓度下，胰岛素刺激的外周葡萄糖摄取增加了约20%。总而言之，这些数据支持IKKbeta代表着治疗2型糖尿病的新靶点的假设。
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.