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 ¹²⁵I-labelled insulin uptake by rat hindlimb muscle and examined how that is affected by adding unlabelled insulin at high concentrations. We used mono-iodinated [¹²⁵I]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 ¹²⁵I-labelled insulin, slowed the movement of ¹²⁵I-labelled insulin from plasma into liver, spleen and heart (p < 0.05, for each) but increased kidney ¹²⁵I-labelled insulin uptake. High concentrations of unlabelled insulin delivered either continuously (insulin clamp), or as a single bolus, significantly decreased skeletal muscle ¹²⁵I-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 ¹²⁵I-labelled insulin clearance.

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.