Made in United Staies of America
Vol. 63, No. 3, February, 1923
I ~~/ ~ Experiments on the mechanism of action of insulin. N. A. MC(CoRMICK,
I/ J. J. R. MACLEOD, K. O'BRIEN and E. C. NOBLE.
When the percentage of blood sugar is measured at half-hour inter-
vals following the injection of insulin in rabbits, the absolute fall is at
first the same, within wide limits, whatever the dose of insulin. Neither
the nutritive condition of the animals nor the method of administration
(subcutaneous or intravenous) makes any significant difference in the
steepness of the curve. The subsequent behavior of the curve depends
partly on the dose of insulin and partly on the glycogen content of the
liver. But even when these are the same in different animals, the
curves may vary considerably, so that no accurate method of physi-
ological assay can be based on measurement of the blood sugar at any
chosen interval following injection. The rapid and uniform fall during
the first half-hour is not due to increased intravascular glycolysis, since
insulin has no effect on the rate of glycolysis in blood removed from the
body. It is not due to polymerization of glucose in the blood, since
hydrolysis of blood removed when the sugar is at its lowest does not
cause any greater increase in reducing power than occurs under the
same conditions in normal blood. The insulin must therefore enter the
tissue cells and create therein a vacuum for glucose, as a result of which
sugar is withdrawn from the blood more quickly than the liver and
muscles can supply it from their stores of glycogen. Since insulin is
known to cause marked glycogen formation in the liver of diabetic dogs,
it is possible that the vacuum for glucose in the tissue cells is in part due
to polymerization of glucose in them, but it is also partly due to in-
creased combustion, since there is usually a marked increase in the
R. Q. of normal, as well as diabetic dogs, and the oxygen consumption
also increases (Dixon and Pember). The R. Q. may rise decidedly
above unity and remain there much longer than can be explained by a
blowing off of (02 due to hyperpnea. This would seem to indicate a
reduction of carbohydrate akin to that which occurs in hibernating
animals during the fall months, while they are converting carbohydrate
into fat. As the effect of insulin wears off, restoration of the sugar
curve depends largely on the glycogen stores, but even in comnpletely
deglycogenated animals restoration also occurs, although more slowly,
indicating that a process of gluconeogenesis is set up.