Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
PLoS One. 2013 May 2;8(5):e61840. doi: 10.1371/journal.pone.0061840. Print 2013.
AIMS/HYPOTHESIS: Impaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO-dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes.
Forearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra-arterial infusion of [4,5-(3)H] L-arginine.
In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [(3)H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics.
These findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport.
目的/假设：心血管疾病中已报道存在 L-精氨酸转运受损，这为一氧化氮（NO）生成减少提供了一种可能的机制。鉴于心血管疾病也与胰岛素抵抗相关，并且已知胰岛素通过依赖于 NO 的途径诱导血管舒张，我们假设异常的胰岛素调节 L-精氨酸转运可能导致糖尿病中的血管功能障碍。
使用静脉闭塞体积描记法测量对照和 2 型糖尿病志愿者的胰岛素和硝普钠（SNP）引起的前臂血流（FBF）反应。通过 HPLC 确定动脉内胰岛素对内臂静脉-动脉 L-精氨酸和相关氨基酸通量的影响。在[4,5-(3)H] L-精氨酸的动脉内输注期间，评估局部给予胰岛素对精氨酸转运的影响。
在对照者中，5 mUnits/min 的胰岛素臂内输注导致 FBF 逐渐升高（p<0.001），而在糖尿病患者中则不明显。支持这一观察结果，我们观察到在对照者中，NO 前体 N-羟基-L-精氨酸的通量也有相应的显著增加（基线与 60 分钟胰岛素：16.2±12.2 与 33.0±13.1 nmol/100 ml 组织/分钟；p<0.01），而在糖尿病患者中则没有观察到增加。此外，胰岛素在对照者中增加了[3H]L-精氨酸从前臂循环中的清除率（基线与胰岛素：123±22 与 150±28 ml/min；p<0.05），但在糖尿病患者中则没有。
这些发现表明，胰岛素抵抗可能通过异常的胰岛素介导的 L-精氨酸转运调节，在 2 型糖尿病中对心血管疾病的发生和发展产生重大影响。
