Pistrosch Frank, Passauer Jens, Fischer Sabine, Fuecker Katja, Hanefeld Markolf, Gross Peter
Nephrology, Department of Medicine, University Hospital Dresden, Dresden, Germany.
Diabetes Care. 2004 Feb;27(2):484-90. doi: 10.2337/diacare.27.2.484.
Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction.
We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp.
Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 +/- 1.3 vs. 8.8 +/- 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 +/- 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginine-acetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01).
Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.
胰岛素抵抗是动脉粥样硬化和心血管疾病死亡率的独立危险因素。然而，胰岛素抵抗导致动脉粥样硬化的机制尚不清楚。可以想象，内皮功能障碍可能与之相关。因此，我们探讨胰岛素抵抗的治疗是否能改善内皮功能障碍。
我们对12例新诊断的2型糖尿病患者进行了一项双盲交叉试验。他们随机接受罗格列酮4mg，每日2次，共12周，以及那格列奈60mg，每日2次，共相同周数。为评估内皮功能障碍的程度，我们采用静脉阻塞体积描记法。我们研究了在有和没有外源性胰岛素的情况下，乙酰胆碱（ACh）引起的血管舒张。药物经肱动脉注入。此外，我们通过正常血糖钳夹法测定胰岛素抵抗。
罗格列酮和那格列奈治疗下的血糖控制相当。与那格列奈相比，罗格列酮使胰岛素抵抗改善了60%。罗格列酮治疗后ACh反应显著增加（罗格列酮和那格列奈治疗后最大前臂血流量分别为12.8±1.3与8.8±1.3ml/100ml；P<0.05），但未达到健康对照者的水平（14.0±0.7ml/100ml）。在罗格列酮组中，外源性胰岛素的共同注入进一步增加了ACh反应。一氧化氮合酶拮抗剂N-单甲基-L-精氨酸-乙酸盐（L-NMMA）在很大程度上阻止了罗格列酮治疗后血管舒张的增加，无论是否存在胰岛素。胰岛素敏感性和血流反应呈正相关（P<0.01）。
胰岛素抵抗是2型糖尿病患者内皮功能障碍的主要原因。罗格列酮可治疗内皮功能障碍和胰岛素抵抗。
