MECHANISMS OF HORMONE ACTIONS
187
tion will therefore be given to insulin, adrenaline, the thyroxine group,
and to the steroids, the estrogens and progesterone.
II. INSULIN
During the last few years several comprehensive reviews dealing with
the mechanism of action of insulin have been published (Bouckaert
and de Duve, 1947; Soskin and Levine, 1946, 1952; Stadie, 1954; Levine
and Goldstein, 1955; Weil-Malherbe, 1955), and the reader is referred
to them for detailed references and for variety of viewpoint. Sanger's
elucidation of the amino acid sequence and the structure of the insulin
molecule is one of the most brilliant chemical achievements of the recent
era (Sanger and Tuppy, 1951; Sanger and Thompson, 1953). However,
thus far the structure of the molecule has remained unrelated to any of
its effects, and no notions as to the mode of action can be derived from
it. Insulin is a simple protein of unit molecular weight of about 6000.
Since the intravenous injection of 4-/¿g/kg body weight lowers the blood
sugar of a susceptible animal about 50% from the initial level, it can
be calculated that approximately 4000 molecules are available per cell of
assumed average volume of 8000 μ
3
, or one molecule for every 2 μ.
3
. The
minimal effective dose of insulin is closer to one-fifth of the above
amount. It is thus evident that we are dealing with a material of the type
associated with active catalysis or the initiation of a chain of reactions.
In certain animal species (dog, cat, rat), complete pancreatectomy
effectively removes all insulin-secreting cells. The syndrome of diabetes
becomes established in the following sequence: the blood sugar rises;
liver glycogen diminishes; liver fat content rises; the blood ß-keto acid
level increases as does the rate of urea formation in the liver; muscle
glycogen levels fall more slowly, and that of the heart and the kidney
tubules rises. The urinary findings of increased excretion of glucose,
ketones, urea, water, and chlorides are all clearly secondary to internal
events. It has been clearly established that kidney functions are themselves normal in experimental diabetes.
The discovery of insulin gave rise to a period of intensive investigation
into the mechanism by which this hormone was able to restore to normal
all the metabolic deviations of the diabetic state. Because of the sequence of events which follows pancreatectomy, it was assumed (correctly in most instances) that practically all the metabolic changes of
diabetes were secondary and more remote consequences of the inability
to "burn" or to "store" sugar, or both (Macleod, 1926). It followed
therefore that the primary effect of insulin was to be sought in the areas
of glucose oxidation and storage. This was the conclusion of the classic
papers of Best, Dale, Hoet, and Marks in 1926 (Best et al, 1926a, b).
187
tion will therefore be given to insulin, adrenaline, the thyroxine group,
and to the steroids, the estrogens and progesterone.
II. INSULIN
During the last few years several comprehensive reviews dealing with
the mechanism of action of insulin have been published (Bouckaert
and de Duve, 1947; Soskin and Levine, 1946, 1952; Stadie, 1954; Levine
and Goldstein, 1955; Weil-Malherbe, 1955), and the reader is referred
to them for detailed references and for variety of viewpoint. Sanger's
elucidation of the amino acid sequence and the structure of the insulin
molecule is one of the most brilliant chemical achievements of the recent
era (Sanger and Tuppy, 1951; Sanger and Thompson, 1953). However,
thus far the structure of the molecule has remained unrelated to any of
its effects, and no notions as to the mode of action can be derived from
it. Insulin is a simple protein of unit molecular weight of about 6000.
Since the intravenous injection of 4-/¿g/kg body weight lowers the blood
sugar of a susceptible animal about 50% from the initial level, it can
be calculated that approximately 4000 molecules are available per cell of
assumed average volume of 8000 μ
3
, or one molecule for every 2 μ.
3
. The
minimal effective dose of insulin is closer to one-fifth of the above
amount. It is thus evident that we are dealing with a material of the type
associated with active catalysis or the initiation of a chain of reactions.
In certain animal species (dog, cat, rat), complete pancreatectomy
effectively removes all insulin-secreting cells. The syndrome of diabetes
becomes established in the following sequence: the blood sugar rises;
liver glycogen diminishes; liver fat content rises; the blood ß-keto acid
level increases as does the rate of urea formation in the liver; muscle
glycogen levels fall more slowly, and that of the heart and the kidney
tubules rises. The urinary findings of increased excretion of glucose,
ketones, urea, water, and chlorides are all clearly secondary to internal
events. It has been clearly established that kidney functions are themselves normal in experimental diabetes.
The discovery of insulin gave rise to a period of intensive investigation
into the mechanism by which this hormone was able to restore to normal
all the metabolic deviations of the diabetic state. Because of the sequence of events which follows pancreatectomy, it was assumed (correctly in most instances) that practically all the metabolic changes of
diabetes were secondary and more remote consequences of the inability
to "burn" or to "store" sugar, or both (Macleod, 1926). It followed
therefore that the primary effect of insulin was to be sought in the areas
of glucose oxidation and storage. This was the conclusion of the classic
papers of Best, Dale, Hoet, and Marks in 1926 (Best et al, 1926a, b).