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Capillary Endothelial Insulin Transport: The Rate-limiting Step for
Insulin-stimulated Glucose Uptake.
Williams IM, Wasserman DH
Submitted Externally on 3/9/2022
Volume : Pages
The rate-limiting step for skeletal muscle glucose uptake is transport from
microcirculation to muscle interstitium. Capillary endothelium poses a barrier
that delays the onset of muscle insulin action. Defining physiological barriers
that control insulin access to interstitial space is difficult because of
technical challenges that confront study of microscopic events in an integrated
physiological system. Two physiological variables determine muscle insulin
access. These are the number of perfused capillaries and the permeability of
capillary walls to insulin. Disease states associated with capillary rarefaction
are closely linked to insulin resistance. Insulin permeability through highly
resistant capillary walls of muscle poses a significant barrier to insulin
access. Insulin may traverse the endothelium through narrow intercellular
junctions or vesicular trafficking across the endothelial cell. Insulin is large
compared with intercellular junctions, making this an unlikely route. Transport
by endothelial vesicular trafficking is likely the primary route of transit.
Studies in vivo show movement of insulin is not insulin receptor dependent. This
aligns with single-cell transcriptomics that show the insulin receptor is not
expressed in muscle capillaries. Work in cultured endothelial cell lines suggest
that insulin receptor activation is necessary for endothelial insulin transit.
Controversies remain in the understanding of transendothelial insulin transit to
muscle. These controversies closely align with experimental approaches. Control
of circulating insulin accessibility to skeletal muscle is an area that remains
ripe for discovery. Factors that impede insulin access to muscle may contribute
to disease and factors that accelerate access may be of therapeutic value for
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