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FEBRuARY 10, 1923] 
NATURE 
189 

large as peas. But, for some reason or other, extracts 
of the pancreas have only occasionally been found to 
have any influence when given to diabetic animals. 
The active constituent is destroyed by some other 
substance, possibly trypsin, contained in suth extracts. 
Since the cells which produce trypsin degenerate 
after tying the ducts, it occurred to Dr. Banting, 
rather more than a year ago, that extracts of such 
organs might contain the active principle sought for, 
free from destruction. Dr. Banting was then in 
medical practice at London, Ontario, but gave up 
his practice and went to Prof. Macleod’s laboratory 
at Toronto to make the necessary experiments on 
animals. Here he was joined by Mr. Best, an assistant 
in the laboratory, by Prof. Macleod himself, and at a 
later date by Dr. Collip and others. The experiments 
were successful. In another way it was found possible 
to prepare active extracts. dt had been noticed that 
the presence of a fcetus protects the mother. The 
islet tissue, as it appears, begins to be functional at 
an earlier date than the secreting cells, so that by 
taking the pancreas of a fcetal calf at the appropriate 
age, the destructive agent was absent. But it was 
clear that these methods could only afford a small 
supply. Hence attempts were made to discover a 
means of preparation from the ordinary ox pancreas. 
Dr. Collip was finally successfully by making use of 
alcohol. The active principle, which it is proposed to 
call “insulin,” is soluble in alcohol of a strength such 
as to precipitate enzymes, proteins, and probably 
other substances, although, like secretin, it is insoluble 
in absolute alcohol. This latter fact gives opportunity 
for further purification from lipoid. It is finally 
obtained in solution in physiological saline, suitable 
for subcutaneous injection. The absence of protein 
is necessary for clinical use, because of the possibility 
of anaphylactic shock, if the injections were omitted 
for a time and then resumed. 
. Passing next to the properties of insulin, it was 
found that if injected subcutaneously into animals 
made diabetic by removal of the pancreas, or indeed 
hyperglycemic in any way, the sugar content of the 
blood was reduced and the glycosuria abolished. 
Moreover, a very interesting fact was discovered. 
The blood sugar can be reduced in normal animals by 
insulin, but if it falls below a certain level (about 
0-045 per cent. in rabbits), nervous symptoms come 
on, and the animal may die in convulsions. These 
symptoms are at once removed by injection of glucose. 
Thus the normal activity of the central nervous 
system depends on the presence of a sufficient con- 
centration of sugar in the blood. It is probable, 
therefore, that sugar is burned in the brain, and 
possibilities of investigating the energy value of the 
cerebral processes associated with mental activity 
open before us. The fact, however, causes a diffi- 
culty in the clinical use of insulin. If too large a dose 
be given, or it be absorbed too rapidly, nervous symp- 
toms make their appearance. Fortunately, they are 
unmistakable by the patient, who can at once have 
recourse to the sugar basin. 
Another important action of insulin is to reduce or 
abolish the presence of acetone and its derivatives in 
the blood and urine—a characteristic sign of the 
diabetic state. These compounds have a toxic action 
NO. 2780, VOL. 111] 
on the nervous system, finally leading to coma and 
death. They are the result of incomplete combustion 
of fat, and are present whenever insufficient sugar is 
being oxidised—in carbohydrate starvation as well 
as in diabetes. It is an interesting fact that neither 
fat nor protein can be properly utilised without carbo- 
hydrate. The oxidation of the former appears to be 
a kind of “ coupled reaction ” with that of sugar, and 
we therefore ask what is the common component ? 
Pyruvic acid or aldehyde, as a stage in the oxidation 
of both, has been suggested. Vahlen put forward the 
view some years ago that the function of the pan- 
creatic hormone was to convert glucose into a simpler 
compound more easily oxidised. These possibilities 
may be accessible to experiment in vitro by the use 
of concentrated solutions of insulin. According to 
some recent work by Winter and Smith in the Bio- 
chemical Laboratory at Cambridge, it seems that 
y-glucose, the reactive ethylene-oxide form of glucose, 
is the first stage, insulin acting as the activator of some 
enzyme in the tissues. In the normal state, the blood 
sugar is in the y-form, presumably not in diabetes. 
The failure to make use of protein in the absence of 
concurrent oxidation of glucose may have some 
bearing on another characteristic of the diabetic state 
—the imperfect healing of wounds. It is pointed out 
by Dr. Formiguera in the British Medical Journal of 
December g last that insulin will be of much value 
in making possible the performance of necessary 
operations in the diabetic—a matter otherwise not 
to be done. Prof. Starling has suggested that its use 
may also make it feasible to transplant grafts of foetal 
pancreas into such cases. Although the work of 
Leo Loeb has made it clear that tissues from another 
individual, unless a very closely related one, degenerate 
sooner or later when transplanted, embryonic tissues 
are not so extremely individualised, and the experiment 
is worth trial. 
Insulin confers on the diabetic liver the power of 
storing glycogen. 
Since the capacity of oxidising glucose is deficient 
in the diabetic animal, an injection of glucose does 
not raise the respiratory quotient ; whereas if insulin 
be given at the same time this happens. Thus we 
have the proof that glucose is actually burned and not 
caused to disappear in some other way. It is further 
shown by Hepburn and Latchford that the excised 
heart of the rabbit consumes more glucose if insulin 
be added to the perfusing solution. Unfortunately, 
it was not shown that the respiratory quotient was 
raised, and the authors have overlooked the fact that 
Starling and Evans in 1914 found in some cases that 
the respiratory quotient of the diabetic heart was 
raised by the addition to the blood of an acid extract 
of the pancreas. It may be remarked that trypsin 
being inactive in acid solution, it was thought to 
avoid destruction of the hormone in this way. Indeed, 
although it is actually destroyed in an alkaline solution 
of trypsin, it is not certain whether it may not be 
oxidised, or destroyed by some agent other than 
trypsin itself. 
Insulin, given to diabetic patients by subcutaneous 
injection, is found to have the same effects as in 
animals, together with an unmistakable improvement 
in condition. Apart from its relieving the serious 
