University of Virginia Health System, PO Box 801410, 450 Ray C. Hunt Drive, Charlottesville, VA 22908, USA.
Diabetologia. 2012 Feb;55(2):450-6. doi: 10.1007/s00125-011-2343-x. Epub 2011 Oct 15.
AIMS/HYPOTHESIS: Insulin's rate of entry into skeletal muscle appears to be the rate-limiting step for muscle insulin action and is slowed by insulin resistance. Despite its obvious importance, uncertainty remains as to whether the transport of insulin from plasma to muscle interstitium is a passive diffusional process or a saturable transport process regulated by the insulin receptor.
To address this, here we directly measured the rate of (125)I-labelled insulin uptake by rat hindlimb muscle and examined how that is affected by adding unlabelled insulin at high concentrations. We used mono-iodinated [(125)I]Tyr(A14)-labelled insulin and short (5 min) exposure times, combined with trichloroacetic acid precipitation, to trace intact bioactive insulin.
Compared with saline, high concentrations of unlabelled insulin delivered either continuously (insulin clamp) or as a single bolus, significantly raised plasma (125)I-labelled insulin, slowed the movement of (125)I-labelled insulin from plasma into liver, spleen and heart (p < 0.05, for each) but increased kidney (125)I-labelled insulin uptake. High concentrations of unlabelled insulin delivered either continuously (insulin clamp), or as a single bolus, significantly decreased skeletal muscle (125)I-labelled insulin clearance (p < 0.01 for each). Increasing muscle perfusion by electrical stimulation did not prevent the inhibitory effect of unlabelled insulin on muscle (125)I-labelled insulin clearance.
CONCLUSIONS/INTERPRETATION: These results indicate that insulin's trans-endothelial movement within muscle is a saturable process, which is likely to involve the insulin receptor. Current findings, together with other recent reports, suggest that trans-endothelial insulin transport may be an important site at which muscle insulin action is modulated in clinical and pathological settings.
目的/假设：胰岛素进入骨骼肌的速度似乎是肌肉胰岛素作用的限速步骤，并且会因胰岛素抵抗而减慢。尽管这一点非常重要，但对于胰岛素从血浆向肌肉间质的转运是被动扩散过程还是受胰岛素受体调节的可饱和转运过程仍存在不确定性。
为了解决这个问题，我们直接测量了大鼠后肢肌肉对（125）I 标记胰岛素的摄取速率，并研究了添加高浓度未标记胰岛素如何影响这一过程。我们使用单碘化 [(125)I]Tyr(A14)-标记胰岛素和 5 分钟的短暴露时间，并结合三氯乙酸沉淀，以追踪完整的生物活性胰岛素。
与生理盐水相比，连续（胰岛素钳夹）或单次推注高浓度的未标记胰岛素均显著提高了血浆中（125）I 标记胰岛素的浓度（p<0.05，每一种情况），减缓了（125）I 标记胰岛素从血浆进入肝脏、脾脏和心脏的速度（p<0.05，每一种情况），但增加了肾脏（125）I 标记胰岛素的摄取。连续（胰岛素钳夹）或单次推注高浓度的未标记胰岛素均显著降低了骨骼肌（125）I 标记胰岛素的清除率（p<0.01，每一种情况）。通过电刺激增加肌肉灌注并不能防止未标记胰岛素对肌肉（125）I 标记胰岛素清除率的抑制作用。
结论/解释：这些结果表明，胰岛素在肌肉内的跨内皮运动是一个可饱和的过程，可能涉及胰岛素受体。目前的发现，以及其他最近的报告，表明跨内皮胰岛素转运可能是在临床和病理情况下调节肌肉胰岛素作用的一个重要部位。
