Potential mechanisms
The primary targets for insulin-stimulated
glucose disposal are skeletal muscle and adipose
tissue and influences on their glucose transport
and metabolism dictate whole-body responsive-
ness to insulin. Muscle, representing some 40%
of body mass, is probably the more important
tissue.
Insulin-mediated glucose uptake into skeletal
muscle proceeds by a series of steps, the first of
which is insulin binding to receptors on the outer
surface of the cell membrane. Glucose transport
is achieved via ‘facilitated diffusion’, a process
which involves a mobile protein carrier (GLUT-
4) which facilitates its transport across the mem-
brane and is thought to be rate-limiting. Besides
its action on glucose transport, insulin inhibits
glycogenolysis, promoting glycogen synthesis.
Muscle glycogen is reduced during exercise, cre-
ating the need for enhanced uptake and storage
and raising the possibility that improved respon-
siveness of this tissue to insulin might exert an
important influence on the body as a whole,
explaining the lower incidence of NIDDM in
physically active people.
It is more than 25 years since the first report of
markedly lower plasma insulin concentrations in
endurance-trained middle-aged men—both in
the fasted state and after an oral glucose load—
than in comparable sedentary men. These find-
ings have generally been interpreted as a sign of
increased insulin sensitivity in peripheral
tissues, since hepatic glucose output is sup-
pressed after glucose ingestion. Later studies
have confirmed this, measuring reduced insulin
secretion and a shift in the insulin/glucose dis-
posal response curve, promoting glucose trans-
port and storage. Whole-body non-oxidative
glucose disposal during glucose infusion is
higher in endurance-trained athletes than in
sedentary controls. Total activity of glycogen
synthase and insulin-stimulated activation of the
enzyme is enhanced as trained muscle adapts to
the increased intracellular availability of glucose
by developing an enhanced capacity for glucose
storage as glycogen.
The mechanisms by which training enhances
44 nutrition and exercise
glucose uptake in skeletal muscle are local rather
than systemic and probably involve changes in
levels of the muscle glucose transporter GLUT-4.
Endurance-trained athletes possess higher levels
of GLUT-4 than sedentary controls and levels are
markedly higher in trained than in untrained
muscle from the same individual, in association
with a higher insulin-stimulated glucose uptake.
Glucose uptake depends on its rate of delivery
to the tissue, however, as well as that tissue’s
responsiveness to insulin. Insulin stimulates
increases in blood flow to muscle in a dose-
responsive manner and this effect could, specu-
latively, be enhanced in athletes because of
improved capillarization.
Following each exercise session, glucose
uptake into skeletal muscle increases. This is
partly an insulin-independent contractile effect
which persists for several hours afterwards but,
in addition, the response to insulin of the glucose
transport system is improved. This usually
lasts longer, for at least 48 h. As stated above,
these may be responses to the need to replenish
muscle glycogen; certainly exhaustive, intermit-
tent glycogen-depleting exercise at 85% V.
o2max.
results in increased non-oxidative glucose dis-
posal when measured 12 h later.
When endurance-trained people refrain from
training, their enhanced insulin action is rapidly
reversed. The timescale of this reversal is not
clear; training effects have been reported to
persist for as little as 36 h but more typically for
about 3 days, so that levels seen in sedentary
people are approached within 1 week. Could the
good insulin sensitivity which characterizes ath-
letes be attributable to residual effects of their last
training session, rather than to any long-term
adaptive effects? The answer to this question is
‘probably not’. Studies have compared the
response of a trained leg to a single session of
exercise with that of an untrained (contralateral)
leg to identical exercise; insulin action was
improved in the trained leg but there was no
effect in the untrained leg. The effect of training
on insulin-mediated glucose disposal in muscle
has therefore been described as a genuine adap-
tation to training—but short-lived.
Whole-body insulin sensitivity is directly and