3. When the pancreas is partially extirpated and the remaining portion, with its vessels attached, sutured to the abdominal wall (yr(yre .sorrs-cl(fume), diabetes fails to appear; but if this engrafted portion of the pancreas is removed later by a now insignificant oper ation, the disease manifests itself. This modification of the experi meat proves that accidental injuries of the sympathetic nerves, etc., which are often unavoidable in intra-abdominal total extirpation of the pancreas, have nothing to do with the production of the diabetes; and more than that, it proves that it is only the removal of the pan creas itself that is responsible for the disease.
4. When about a tenth part of the pancreas is left in a function ating condition, a mild form of diabetes ensues. The glycosuria is slight and occurs only after the ingestion of carbohydrates. But if the remaining portion of the gland becomes subsequently obliterated, then diabetes in severe form follows. When more than one-tenth of the gland is left behind with power of performing its functions, no diabetes ordinarily results.
5. The relation which exists between the pancreas and excretion of sugar from the organism does not depend upon the action of the pancreatic juice, for diabetes does not occur in cases of simple shut ting off of the latter from the intestine, nor yet when the fluid escapes through a cutaneous fistula.
6. The influence of the pancreas upon the excretion of sugar ap pears to be, at least in dogs, a specific one, that is to say, no organ other than the pancreas possesses it. Some authors (de Renzi and Reale) have, indeed, asserted that they obtained the same result through extirpation of the salivary glands and through resection of the entire duodenum. Nevertheless Minkowski, in corroboration of earlier experiments of Fehr, failed to observe this. It is true that sometimes, even in his hands, glycosuria appeared after the opera tions just mentioned; but it was only moderate in degree and rapidly disappeared, acting exactly like those forms of glycosuria observed after numerous operative procedures in animals (see above) ; it was an experimentally produced glycosuria, but not diabetes mellitus.
We see, now, from the above-enumerated experimental facts that, in the body of the dog (and probably also of many other animals), the pancreas is necessary for the regulation of the normal sugar econ omy. After excluding all other possibilities, -the discoverers have formulated the following hypotheses : Either some substance, which has an injurious influence upon the conversion of sugar, collects in the organism after extirpation of the pancreas, or else, after this operation, there is some substance want ing or some function is abolished which •under normal conditions serves to facilitate the conversion of carbohydrate bodies.
The expressions in these formulas are very general and indefinite, but that is of necessity, since great caution is demanded in pronounc ing upon these questions. Something definite can nevertheless be said as to the way in which the economy of the carbohydrates is clis turbed by extirpation of the pancreas. In all the experiments made the fact is evident that the grape sugar taken in with the food, as well as that found in the organism itself, is no longer consumed in a nor mal way after removal of the pancreas, while there is no evidence going to show that there is also a morbidly increased new formation of sugar. The important point is therefore established that the de posit of glycogen in the liver and muscles does not normally take place after extirpation of the pancreas. The animals may be fed abundantly with starchy materials without more than traces of glyco gen being found in these organs. The only exception to this is when the animals are supplied with levulose (fruit sugar) ; in this case the liver and muscles become richly supplied with glycogen. This
last-mentioned fact is especially interesting since clinical experience has long since shown that the human subject of diabetes mellitus suffers from only a slight increase of sugar in the urine after the in gestion of levulose (see below). The assumption that there is a cer tain internal relation between a diminished deposition of glycogen and a diminished consumption of carbohydrates in the organism re ceives some support from this experience.
Naturally the endeavor has been made to obtain a more profound theoretical understanding of the way in which these results of extir pation of the pancreas are brought about. But up to the present Lepine of Lyons is the only one who has pursued the subject further along experimental lines. His theory is that the pancreas produces a ferment which enters the circulation and causes a breaking up of the grape-sugar molecule within the blood. L6pine calls this sub stance "glycolytic ferment." After extirpation of the pancreas this ferment is not present; the sugar therefore accumulates undestroyed in the blood and from the hyperglycemia so produced glycosuria results. The experiments upon which Lepine bases this opinion, which were carried out for the most part in collaboration with Barral, were conducted in the following way. He abstracted a certain amount of blood from the vascular system, and immediately heated the half of it to 54° C. (129.2° F.), destroying thereby the glycolytic ferment. He then put this portion of the blood, as well as the remaining portion which had not been heated, into an incubator in a temperature of 89' C. (1(J2.2° F.), and examined both samples for sugar after the lapse of an hour. When Lepine used the blood of healthy animals and men, he found a much smaller percentage of sugar in the not-heated than in the heated sample of blood; but when the blood of an animal from which the pancreas had been removed was taken, the difference in the proportion of sugar contained in two samples was slight. He reasoned from this that there was a decrease in the amount of glycolytic ferment after extirpation of the pancreas. He also extended his investigations to men, and found that the con ditions were the same in individuals suffering from diabetes mellitus as in dogs without the pancreas.
If Lepine's researches had been rightly made, and if we could ac cept the conclusions which he derived from them, they would consti tute a most important advance in our knowledge of pancreatic diabetes. But the matter is not so favorable. In the first place it must be re marked that many well-known investigators, skilled in chemical ma nipulations, have repeated Lepine's experiments without obtaining his results. Among these are Arthus, Gaglio, Seegen, Kraus, and Minkowski. The contradictions relate.to the fact alleged by Lepine of the rapid disintegration of sugar in•normal blood, as well as to the assumed difference in this respect between normal and diabetic blood. It has further been held that we cannot argue from the results of test tube experiments as to the conditions present in living blood circu lating in the vessels of the body. Without doubt the whole question demands further study and elucidation, but it cannot be denied, that at present the weight of opinion is opposed to Lepine's theory.
_ From the description just given of the experimentally produced pancreatic diabetes it can well be seen that the discovery of von Mering and Minkowski is of very great importance. It will be our task later to determine how much light has been thrown upon the question of the etiology of diabetes mellitus in man by the results of these experiments.