MECHANISMS OF HORMONE ACTIONS
197
on fructose utilization was demonstrable only in the absence of glucose,
the mutual inhibitory action of the sugars must be taken into account in
studying the properties of the glucose intake system. In view of our
own data showing no definitive effect of insulin on the utilization of
mannose, and those of C. and G. Cori (1929) on eviscerated rats showing no insulin effect on the disposal of fructose and mannose, it is possible that certain species (e.g., rabbit) possess a sugar transfer system
which differs in structural specificity from that of the dog or the rat.
The hexokinase system of the extrahepatic tissues of the dog exhibits
a high order of activity. Even if the blood sugar is raised to 1200 mg%
(in the presence of insulin) there is only an insignificant amount of free
glucose in the intracellular compartment of skeletal muscle. This was
estimated by using the chloride space as a measure of the extracellular
compartment, and glucose oxidase for the specific estimation of the free
hexose (Levine and Goldstein, 1952). Park demonstrated that under
certain conditions insulin can be shown to increase the level of free
glucose in skeletal muscle and heart (Park et al, 1955; Park and Johnson, 1955). This was done either by overwhelming the hexokinase
system with more glucose than it could handle, or by keeping tissues
at a low temperature at which hexokinase activity was strongly reduced,
while the transfer action of insulin was not affected to the same degree.
This was the first demonstration that the postulated action of insulin
applies to glucose as well as to other sugars.
The work just summarized allows the conclusion that insulin acts (at
least in the peripheral tissues of the dog, rabbit, and rat) to facilitate the
transfer of extracellular free glucose into the cell. The subsequent fate
of the sugar would depend upon the state of the enzymatic apparatus.
Several areas of inquiry now become pertinent:
1. What is the nature of the insulin-sensitive glucose transfer mechanism? Are any deductions possible at present, and what lines of investigation are necessary to study such mechanisms?
2. Is the effect of insulin here described actually of the primary type?
Does it account for all or most of the observed effects on insulin administration or removal? How does this action of insulin relate to that
of the so-called contra-insulin factors of the pituitary and of the adrenal
cortex?
3. Is the action of insulin on the handling of sugar by the liver the
same or similar to the one described for the extrahepatic tissues?
The work of Stadies laboratory (Stadie et al, 1949, 1950, 1952, 1953)
since 1949 makes it evident that insulin and certain other hormonal
factors are "fixed" by the cell (surface?) and probably exert their effects
197
on fructose utilization was demonstrable only in the absence of glucose,
the mutual inhibitory action of the sugars must be taken into account in
studying the properties of the glucose intake system. In view of our
own data showing no definitive effect of insulin on the utilization of
mannose, and those of C. and G. Cori (1929) on eviscerated rats showing no insulin effect on the disposal of fructose and mannose, it is possible that certain species (e.g., rabbit) possess a sugar transfer system
which differs in structural specificity from that of the dog or the rat.
The hexokinase system of the extrahepatic tissues of the dog exhibits
a high order of activity. Even if the blood sugar is raised to 1200 mg%
(in the presence of insulin) there is only an insignificant amount of free
glucose in the intracellular compartment of skeletal muscle. This was
estimated by using the chloride space as a measure of the extracellular
compartment, and glucose oxidase for the specific estimation of the free
hexose (Levine and Goldstein, 1952). Park demonstrated that under
certain conditions insulin can be shown to increase the level of free
glucose in skeletal muscle and heart (Park et al, 1955; Park and Johnson, 1955). This was done either by overwhelming the hexokinase
system with more glucose than it could handle, or by keeping tissues
at a low temperature at which hexokinase activity was strongly reduced,
while the transfer action of insulin was not affected to the same degree.
This was the first demonstration that the postulated action of insulin
applies to glucose as well as to other sugars.
The work just summarized allows the conclusion that insulin acts (at
least in the peripheral tissues of the dog, rabbit, and rat) to facilitate the
transfer of extracellular free glucose into the cell. The subsequent fate
of the sugar would depend upon the state of the enzymatic apparatus.
Several areas of inquiry now become pertinent:
1. What is the nature of the insulin-sensitive glucose transfer mechanism? Are any deductions possible at present, and what lines of investigation are necessary to study such mechanisms?
2. Is the effect of insulin here described actually of the primary type?
Does it account for all or most of the observed effects on insulin administration or removal? How does this action of insulin relate to that
of the so-called contra-insulin factors of the pituitary and of the adrenal
cortex?
3. Is the action of insulin on the handling of sugar by the liver the
same or similar to the one described for the extrahepatic tissues?
The work of Stadies laboratory (Stadie et al, 1949, 1950, 1952, 1953)
since 1949 makes it evident that insulin and certain other hormonal
factors are "fixed" by the cell (surface?) and probably exert their effects