Metabolism in diabetes mellitus

By Francis Gano Benedict, Elliott Proctor Joslin

Perhaps no chronic disease makes such rapid inroads on health, strength, and weight as does diahetes. The large amounts of sugar in the urine, the polydipsia, polyphagia, and polyuria are observations so common in many cases that it is not at all surprising that the gross metabolism during diabetes should have been studied by many investigators.

In the earlier investigations on metabolism in diabetes, two types of apparatus have been employed, the respiration chamber and the mouth-breathing appliance. The conditions obtaining in studies with these two types of apparatus are quite different. In the respiration chamber the subject is sitting up or lying in bed under conditions of normal rest, although there is more or less muscular activity. With the mouth-breathing appliance, on the other hand, he is lying quietly under almost enforced muscular rest, with a minimum amount of exertion.

The conditions vary so widely, especially with regard to muscular activity, that it is usually not practicable to compare these two classes of experiments with any degree of satisfaction. It has been shown, however, in a large number of experiments at Wesleyan University, that the results obtained for the earbon-dioxide elimination and the oxygen consumption during the period when the subjects are in the respiration chamber and asleep may be compared with those obtained by the use of the special mouth-breathing appliances, particularly the Zuntz-Geppert apparatus.1 In considering the results of the earlier studies made on the metabolism in diabetes, we will therefore first take up those experiments carried out by the chamber method, and while experiments with the Zuntz-Geppert apparatus were made as early as 1891, the discussion of the results thus obtained will be deferred until all researches with the chamber method are presented.

The large respiration chamber of Pettenkofer,’ which was constructed in Munich in 1862, was the first apparatus of this type with which experiments on diabetes were made, and as used by Pettenkofer and Voit ordinarily gave remarkably satisfactory and accurate determinations for the carbon-dioxide excretion of man.

‘ Benedict and Carpenter, Carnegie Institution of Washington, Publication No. 126, pp. 166 and 182. See also Durig, Physiologlsche Ergebnisse der im Jahre 1906 Durchgefiihrten Monte Rosa-Expedition. Ueber den Erhaltungsumsatz. Besonders Abgedruckt aus deffi LXXXVI. Bande der Denkschriften der Mathematisch-Naturwissenschaftlichen Klasse der Kaiserlichen Akademie der Wissenschaften. Wien, 1909.

‘Pettenkofer, Ann. der Chem. u. Pharm., 1862, Supp. Bd. 2, pp. 1-52.

Certain fundamental errors entered into their determination of the water vaporized, and the determinations of the oxygen consumption of man were of necessity confined to those made by the indirect method, hence all the errors incidental to the determinations of the carbon-dioxide elimination, water vaporization, and changes in body-weight affected the results for the oxygen consumption. A critical examination of their data shows that while we can rely for the most part upon the determination of the carbon-dioxide elimination, little reliance can be placed on the determination of the water-vapor and practically none upon that for the oxygen consumption.

Until very recently the oxygen consumption of a subject experimented upon in the respiration chamber could only be determined indirectly, but the direct determination of this factor has also now been made possible. The method used for the indirect determination of the oxygen consumption may be expressed by the formula a = b + c — d, in which a is the amount of oxygen consumed out of the air, b the carbon dioxide produced, c the water vaporized, and d the loss in weight of the body expressed in grams. The determination of the oxygen consumption by this method, therefore, involves an extremely accurate knowledge of these factors. A recent article by one of us * has considered in great detail the difficulties incidental to a careful and accurate determination of the indirect method of determining the oxygen consumption, particularly in experiments on man. With experiments on small animals, Haldane” has developed this method to the highest degree of perfection so that it is possible to weigh not only the animal but also the total respiration chamber itself. With man, however, it is necessary to weigh the body of the man while inside the respiration chamber, and the hygroscopic nature of the bed and bedding, furniture, etc., necessitates an accurate record of the changes in weight of this material, also.

As a result of a large number of 24-hour experiments in the respiration apparatus at Wesleyan University, it was found that an accurate determination of the oxygen consumption by the indirect method was extremely difficult. The amount of furniture and hygroscopic material in the Wesleyan University chamber was very much less than that inside the chamber of Pettenkofer and Voit and provision was made, also, for weighing the subject, furniture, bedding, etc., in the chamber by means of scales outside. Even with these more modern appliances, however, it was found 40 years after the experiments of Pettenkofer and Voit that the indirect determination of the oxygen consumption still remained an extremely difficult task, and only by the expenditure of a large amount of time in the development of special technique and special appliances has it been possible to carry out with man a few experiments in which a comparison has been made of the direct and indirect methods for determining the oxygen consumption. Fortunately it has been possible to prove that under these extraordinary conditions as to technique and apparatus the indirect determination of the oxygen

1 Benedict, Am. Joiirn. Physiol., 1910, 26, p. 15 ‘Haldane, Journ. Physiol., 1892, 13, p. 419.

consumption agrees with the direct determination, though experience with both methods has shown that only the direct determination is practicable in researches on the metabolism of man.

In 1867, Pettenkofer and Voit’ made the first notable contribution to the study of total metabolism in diabetes, in which they gave the results of a series of experiments on a young man with severe diabetes. The subject was 21 years old and had formerly worked on a farm. Between August, 1865, and August, 1866, seven 24-hour experiments were made with him, in which the total intake and output were measured, and complete analyses made of the food, feces, urine, and respiratory products, including an indirect determination of the oxygen consumption. The experiments are not numbered in chronological order but the first experiment reported by them was the fasting experiment of February 1, 1866. In order to make the fast as little trying as possible for the subject, they administered 35.9 grams of meat extract with 22.3 grams of salt and 2590 grams of water. All the other experiments were made with diets varying in the amount of protein and in the total amount of food ingested. The results of the seven experiments are given in table 1.

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