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Insulin exits skeletal muscle capillaries by fluid-phase transport.
Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS,
Submitted Externally on 2/19/2018
The Journal of clinical investigation
Volume : Pages
128 : 699 - 714
Before insulin can stimulate myocytes to take up glucose, it must first move
from the circulation to the interstitial space. The continuous endothelium of
skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The
mechanism by which insulin crosses this continuous endothelium is critical to
understand insulin action and insulin resistance; however, methodological
obstacles have limited understanding of endothelial insulin transport in vivo.
Here, we present an intravital microscopy technique to measure the rate of
insulin efflux across the endothelium of SkM capillaries. This method involves
development of a fully bioactive, fluorescent insulin probe, a gastrocnemius
preparation for intravital microscopy, an automated vascular segmentation
algorithm, and the use of mathematical models to estimate endothelial transport
parameters. We combined direct visualization of insulin efflux from SkM
capillaries with modeling of insulin efflux kinetics to identify fluid-phase
transport as the major mode of transendothelial insulin efflux in mice.
Model-independent experiments demonstrating that insulin movement is neither
saturable nor affected by insulin receptor antagonism supported this result. Our
finding that insulin enters the SkM interstitium by fluid-phase transport may
have implications in the pathophysiology of SkM insulin resistance as well as in
the treatment of diabetes with various insulin analogs.
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