Dept. of Medical Biophysics, Univ. of Western Ontario, London, ON, N6A 5C1, Canada.
Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H1661-70. doi: 10.1152/ajpheart.01239.2009. Epub 2010 Mar 5.
In humans, prediabetes is characterized by marked increases in plasma insulin and near normal blood glucose levels as well as microvascular dysfunction of unknown origin. Using the extensor digitorum longus muscle of 7-wk inbred male Zucker diabetic fatty rats fed a high-fat diet as a model of prediabetes, we tested the hypothesis that hyperinsulinemia contributes to impaired O(2) delivery in skeletal muscle. Using in vivo video microscopy, we determined that the total O(2) supply to capillaries in the extensor digitorum longus muscle of prediabetic rats was reduced to 64% of controls with a lower O(2) supply rate per capillary and higher O(2) extraction resulting in a decreased O(2) saturation at the venous end of the capillary network. These findings suggest a lower average tissue Po(2) in prediabetic animals. In addition, we determined that insulin, at concentrations measured in humans and Zucker diabetic fatty rats with prediabetes, inhibited the O(2)-dependent release of ATP from rat red blood cells (RBCs). This inability to release ATP could contribute to the impaired O(2) delivery observed in rats with prediabetes, especially in light of the finding that the endothelium-dependent relaxation of resistance arteries from these animals is not different from controls and is not altered by insulin. Computational modeling confirmed a significant 8.3-mmHg decrease in average tissue Po(2) as well as an increase in the heterogeneity of tissue Po(2), implicating a failure of a regulatory system for O(2) supply. The finding that insulin attenuates the O(2)-dependent release of ATP from RBCs suggests that this defect in RBC physiology could contribute to a failure in the regulation of O(2) supply to meet the demand in skeletal muscle in prediabetes.
在人类中，前驱糖尿病的特征是血浆胰岛素显著增加，血糖水平接近正常，以及来源不明的微血管功能障碍。我们使用高脂饮食喂养的 7 周龄近交雄性 Zucker 糖尿病肥胖大鼠的伸趾长肌作为前驱糖尿病的模型，检验了高胰岛素血症导致骨骼肌氧供应受损的假说。我们通过活体视频显微镜，确定了前驱糖尿病大鼠伸趾长肌毛细血管的总氧供应减少到对照组的 64%，表现为每个毛细血管的氧供应率降低，氧提取率增加，导致毛细血管网络静脉端的氧饱和度降低。这些发现表明前驱糖尿病动物的平均组织 Po2 较低。此外，我们还确定胰岛素在人类和前驱糖尿病 Zucker 糖尿病肥胖大鼠中测量的浓度，抑制了大鼠红细胞 (RBC) 中氧依赖性 ATP 的释放。这种不能释放 ATP 的能力可能导致前驱糖尿病大鼠观察到的氧供应受损，尤其是鉴于发现这些动物的阻力动脉的内皮依赖性舒张与对照组没有区别，并且不受胰岛素影响。计算模型证实，平均组织 Po2 显著降低了 8.3mmHg，并且组织 Po2 的异质性增加，暗示氧供应调节系统的失效。胰岛素减弱 RBC 中氧依赖性 ATP 释放的发现表明，这种 RBC 生理学缺陷可能导致在前驱糖尿病中调节氧供应以满足骨骼肌需求的失败。
