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/jci200214955
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发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Hundal, RS;Petersen, KF;Shulman, GI
最近的研究表明，丝氨酸激酶IKK β的脂肪酸依赖性激活在胰岛素抵抗的发病机制中起关键作用，在组织炎症中起关键作用。高剂量的水杨酸盐最近被证明可以抑制IKK β活性，因此可能改善2型糖尿病患者的胰岛素抵抗和葡萄糖耐量。为了证实这一假设，我们研究了9名2型糖尿病患者服用阿司匹林（类似于7 g/d）治疗前后2周的情况。受试者接受混合餐耐量试验和[6，6-H-2（2）]葡萄糖高胰岛素-正常血糖钳夹试验，以评估治疗前后的葡萄糖转换。尽管体重没有变化，但大剂量阿司匹林治疗导致空腹血糖降低约25%，总胆固醇和C反应蛋白降低约15%，甘油三酯降低约50%，胰岛素清除率降低约30%。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%。阿司匹林治疗还导致肝脏葡萄糖生成的基础速率降低20%，在钳夹期间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20%。总之，这些数据支持IKK β代表治疗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 rest this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (similar to7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-H-2(2)]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a similar to25% reduction in fasting plasma glucose, associated with a similar to15% reduction in total cholesterol and C-reactive protein, a similar to50% reduction in triglycerides, and a similar to30% 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 similar to20% and similar to50%, respectively. Aspirin treatment also resulted in a similar to20% reduction in basal rates of hepatic glucose production and a similar to20% 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.