Chapter XIII: Front Matter (13)

Crampy pains in the legs and facial paralysis are among the nervous symptoms sometimes present, and the term diabetic neuralgia has been applied to a special form of neuralgia peculiar to this disease. It is characterized by its acuteness, stubbornness, and symmetry. Its favorite seats are the inferior dental nerves and the sciatics. Greisinger referred to the frequency of sciatica in 1859, Braun again in 1868, and others still later; but Worms in 1881 established the close relation between the two conditions and the features described. Most recently (1884), Cornillon[19] collected 22 cases of diabetic neuralgia, and has further elaborated the study. Believing that diabetes affects particularly those persons who have had serious attacks of rheumatism and gout, he is inclined to think the neuralgia as much due to uricæmia as to hyperglycosuria, and that these conditions cause, not neuritis, but transitory lesions in the nerve-centres, but whether in the membranes or gray or white matter is undetermined.

[Footnote 19: "Des nevralgies diabétiques," _Revue de Médecine_, 1884, iv. 213-230.]

That the phenomena of acetonæmia are those of a toxic agent or agents in the blood derived from the sugar there present is generally conceded, although Sanders and Hamilton,[20] after a study of the clinical histories and the result of autopsies in several cases, are disposed to ascribe diabetic coma to slow carbonic-acid poisoning due to fat embolism of the pulmonary vessels. So far as I know, these conclusions have not been reached by any other observers. R. H. Fitz[21] and Louis Starr[22] have each reported cases of diabetic coma with lipæmia, carefully studied with this point in view, without finding any facts to sustain the carbonic-acid theory.

[Footnote 20: _Edinburgh Med. Journal_, July, 1872.]

[Footnote 21: "Diabetic Coma; its relations to Acetonæmia and Fat Embolism," _Boston Medical and Surgical Journal_, vol. cvi. p. 24, Feb. 10, 1881.]

[Footnote 22: "Lipæmia and Fat Embolism in Diabetes Mellitus," _New York Medical Record_, vol. xvii., 1880, p. 477.]

Alterations in the Blood.--The blood of diabetics is variously charged with sugar, which may be in such quantity as to impart a viscidity and higher specific gravity to the plasma, which has reached 1033, the normal being 1028. On the other hand, analyses have sometimes failed to discover sugar in the blood after death, the result, probably, of the tendency of the sugar to rapid disintegration. Alcohol and acetone, or {207} acetone-producing substance (aceto-acetic acid), are occasionally present as the products of such decomposition, to which are ascribed the symptoms of acetonæmia already discussed.

The presence of fat in the blood of diabetics was noted by the earliest students of the disease. It is sometimes sufficient in amount to produce a milky appearance of the serum, while the analyses of Simon revealed a quantity of 2 to 2.4 per cent., the normal being 1.6 to 1.9 per cent. The fat thus present is said to be sometimes sufficient to cause fat embolism in the capillaries of the lungs, and cases of this condition have been reported by Sanders and Hamilton,[23] Louis Starr,[24] and Rickards.[25] Ralfe ascribes the lactescent appearance of the blood to the action of the aceto-acetic acid, since acetic will give a milky appearance when agitated with a dilute and slightly alkaline mixture of fatty matter at 100°, and the injection of acids into the blood of animals leads to the increase of fatty matter in the blood and fatty infiltration of tissues.

[Footnote 23: _Loc. cit._]

[Footnote 24: _Loc. cit._]

[Footnote 25: _Birmingham Med. Review_, Jan., 1882.]

It must be admitted that the mode in which this lipæmic state of the blood is brought about is imperfectly understood, and whether it be by some chemical agency of the kind described by Ralfe, or by rapid absorption of the subcutaneous fat, or from an imperfect oxidation of absorbed fat, is undetermined. Possibly all may contribute.

Albert G. Heyl[26] has described an altered appearance of the retinal vessels recognizable by the ophthalmoscope, which he ascribes to the fatty blood-plasma at the periphery of the blood-current, the normal plasma being invisible on account of its transparency.

[Footnote 26: For a detailed description of this appearance, with a colored lithograph depicting it, see the author's work on _Bright's Disease and Diabetes_, p. 262.]

The red blood-discs are diminished and their ratio to the white corpuscles altered. In a count by F. P. Henry, in Louis Starr's case, the number of red discs was 4,205,000 to a cubic millimeter, the normal being at least 5,000,000; the white were 50,000 to a cubic millimeter, or 1 white to 84 red, instead of 1 to 350 or 500.

Changes in the Urine.--The most important changes in the urine are its increase in quantity and the presence of sugar. The variations in the former are extreme, being from an amount which but slightly exceeds the normal to as much as 50 pints (23.65 liters) in twenty-four hours, and even more. The quantity is of course limited by the fluid ingested, and although it may exceed this amount for a day or more, it cannot do so for any length of time. It is generally a little less. The more usual quantity in the twenty-four hours is from 70 to 100 ounces (210 to 300 cc.).

The quantity of sugar varies greatly in different cases and at different times in the same case. The maximum quantity reported by Dickinson was 50 ounces, or 1500 grammes, in twenty-four hours. The proportion may reach as much as 15 per cent., but the more usual amounts are from 1 to 8 per cent., or from 5 to 50 grains (.324 to 3.24 grams) to the fluidounce, or from 300 to 4000 grains (19.44 to 260 grams) in the twenty-four hours.

It is important to know that intercurrent febrile disease may produce a decided diminution in the daily quantity of urine, and of the sugar contained in it. A similar decrease, and even disappearance, is said to take place sometimes toward the fatal termination of a case.

{208} The effect of exercise upon the sugar secretion is not uniform. Bouchardat and Kuelz have noted a diminution, and even disappearance, of sugar from urine as its result, and it is reasonable to suppose that judicious exercise is at least without harmful effect, while it is certain too that muscular exercise, if excessive, will increase glycosuria.

Changes in diet of course modify the secretion of sugar, starches and saccharine foods increasing it, while nitrogenous and oily foods diminish it. So, too, the urine secreted on rising in the morning has almost always less sugar in it than that passed on retiring; and it is not rare to find no sugar in urine passed on rising, when that passed on retiring at night may contain a small amount of sugar--from ¼ to 1 per cent. On the other hand, I have found a small amount of sugar in the morning urine when the evening urine contained none. Anxiety and excitement both increase the proportion of sugar.

Inosite, or muscle-sugar, is sometimes associated in urine with diabetic sugar, and occasionally replaces it. So, too, in experiments upon animals puncture of the fourth ventricle is sometimes followed by inosuria instead of glycosuria, and in corresponding organic disease of the brain the same thing is observed. The substitution of grape-sugar by inosite in the course of diabetes is considered by Laboulbène[27] a favorable change.

[Footnote 27: "Note sur l'Inosurie, succédant au diabète glycosurique, et paraissant avoir une action favorable," _L'Union Médicale_, Oct. 14, 1883.]

As would be expected, the specific gravity of saccharine urine is usually high--most frequently from 1025 to 1040--and Bouchardat noted a specific gravity of 1074 in one instance. On the other hand, I have found sugar easily detectable in urine with a specific gravity as low as 1010. Pavy records an instance of the same specific gravity, and Dickinson one in which the specific gravity was as low as 1008. It is to be remembered that the sugar is rapidly destroyed when fermentation sets in. A coincident diminution in the urea and other solids of the urine will reduce the specific gravity of a saccharine urine otherwise heavier.

The depth of color of diabetic urine is inversely as the quantity passed. Hence, when this is very large the urine is pale, and even almost colorless, but it may still contain considerable amounts of sugar and possess a decided color, quite as deep as that of urine passed in smaller quantity. When exposed to the air, diabetic urine becomes rapidly turbid from the growth of fungi, including the yeast fungus and penicilium glaucum.

The odor of diabetic urine just passed is usually in no way peculiar, but as fermentation progresses an acetous odor is developed, which is ascribed to acetic acid. At other times the odor is quite peculiar, being spoken of as vinous or compared to that of sour beer, stale fruit, alcohol, chloroform, or, as by one of my patients, to sweetbrier.

Diabetic urine has almost invariably an acid reaction, which becomes more decided as fermentation progresses. As a consequence of this increased acidity, and sometimes independent of fermentation-changes, the urine deposits a sediment of uric acid, but with this exception diabetic urine is generally free from sediment. Diabetic patients on a meat diet sometimes have a good deal of uric acid from this source.

Albuminuria may coexist with glycosuria, but is not generally found until late in the disease, after changes in the kidney begin to make their {209} appearance, unless, as may happen, glycosuria supervenes upon primary renal disease.

Alcohol and acetone, or an acetone-yielding substance--aceto-acetic acid--are sometimes found in diabetic urine. They are products of the breaking up of sugar, but chemists do not explicitly agree as to the exact method in which acetone originates in the organism. First recognized in the distillate of urine and blood of a diabetic patient by Petters[28] through its physical properties, odor, combustibility, etc., rather than by actual isolation, it was further investigated by Kaulich,[29] Gerhardt,[30] Rupstein,[31] and Markownikoff,[32] who obtained it in an impure state from urine; by Deichmüller and Tollens,[33] whose isolated substance was pure, and finally most recently by Jaksch[34] and Penzoldt.[35] The former found it not only in diabetic urine, but also in that of fever, and even of carcinoma. The latter found it by the indigo test in but 18 out of 22 diabetics, and by the iodoform test, either decidedly or feebly, in 20 out of 20; in 3 out of 11 cases of typhoid fever, in 6 out of 7 cases of pneumonia, in none of 6 cases of phthisis, in 1 out of 3 cases of measles, and in 1 case of cerebro-spinal meningitis. Finally, v. Jaksch has been led to believe, from his extensive investigations, that acetone is a constant and normal product of tissue-change, although Penzoldt considers such conclusion scarcely justified.

[Footnote 28: _Prager Vierteljahrschrift_, xiv. 3, 1857, S. 88.]

[Footnote 29: _Ibid._, xvii. 3, 1860, S. 59.]

[Footnote 30: _Wiener Med. Presse_, No. 28, 1865.]

[Footnote 31: _Centralbl. für d. med. Wiss._, No. 55, 1874.]

[Footnote 32: _Liebig's Annalen_, Bd. 182, S. 362.]

[Footnote 33: _Ibid._, Bd. 209, S. 25.]

[Footnote 34: _Zeitschrift für physiol. Chemie_, vi. 6.]

[Footnote 35: "Beiträge zur Lehre von der Acetonurie und von verwandten Erscheinungen," _Deutsch. Archiv für klin. Med._, xxxiv., 2 Oct., 1883, S. 127.]

Gerhardt early discovered a substance in the urine of diabetics and habitual drinkers which struck a deep-red reaction with chloride of iron. This he considered was the source of acetone, and was probably ethyl diacetate or diacetic ether, which by decomposition yields equal molecules of acetone and alcohol; thus:

C_{4}H_{5}O_{3}C_{2}H_{5} + H_{2}O = C_{3}H_{6}O + CO_{2} +
C_{2}H_{6}O.

Ethyl diacetate. Water. Acetone. Alcohol.

This view is still held by some, but others, in view of the recent discovery of Deichmüller and Tollens,[36] that diabetic urine when distilled yields decidedly more acetone than alcohol, have suggested that the substance is derived from aceto-acetic acid.

[Footnote 36: _Loc. cit._]

The first test suggested for acetone was Gerhardt's chloride-of-iron test. A solution of chloride of iron added to urine containing acetone strikes a burgundy-red color. But this reaction occurs with so many substances that it cannot be considered entirely reliable. Ralfe's modification of Lieben's iodoform test[37] is made as follows: About a fluidrachm (3.7 c.c.) of liquor potassæ, containing 20 grains (1.2 grams) of iodide of potassium, is placed in a test-tube and boiled; a drachm (3.7 c.c.) of the suspected urine is then carefully floated upon the surface. When the urine comes in contact with the hot alkaline solution a ring of phosphates is formed, and after a few minutes, if acetone or its allies are present, the ring will become yellow and studded with yellow dots of iodoform, which, in turn, will sink through the ring of phosphates and deposit itself at the bottom of the test-tube. A number of other substances {210} produce the iodoform reaction, but only one of these, lactic acid, is likely to be met in urine.

[Footnote 37: _Clinical Chemistry_, Philadelphia, 1884, p. 100.]

The perspiration, saliva, exudations, and effusions in diabetic cases have all been found, at times, to contain sugar.

DURATION.--Diabetes is a disease of which the duration is measured by months and years, and although cases are reported in which death supervened in from six days to six weeks after the recognition of the disease, it is evident that such periods do not necessarily measure its actual duration. The disease may have existed some time before coming under observation. On the other hand, a case is reported by Lebert which lasted eighteen years; another, under the successive observation of Prout and Bence Jones, sixteen years; and a third, under Bence Jones and Dickinson, fifteen years. The younger the patient the shorter usually is the course run and the earlier the fatal termination. Yet I have known a girl of twelve recover completely. After middle age the disease is usually so easily controlled by suitable dietetic measures, if the patient is willing to submit to them, that its duration is only limited by that of an ordinary life, while carelessness in this respect is apt to be followed by early grave consequences.

COMPLICATIONS.--The almost sole complication of diabetes mellitus is the tubercular phthisis which so often terminates it. Indeed, it is doubtful whether this complication should not be regarded as a consequence, as should also the boils, gangrenous processes, and ophthalmic conditions which have been mentioned under Symptomatology. Jaundice has occurred three times in my experience up to the present time. Senator says that when not an accidental complication due to a catarrh of the duodenum it may result from compression of the biliary capillaries by the overloaded blood-vessels and enlarged gland-cells of the liver. In one of my cases, in which jaundice appeared to be the initial symptom, but which disappeared some months before death, the autopsy revealed atrophy of the liver. It is well known that pancreatic disease, especially cancer, is apt to be accompanied by jaundice, and as pancreatic disease is often at the bottom of diabetes, it will similarly account for the jaundice, while the presence of jaundice may also suggest a pancreatic diabetes.

DIAGNOSIS, INCLUDING THE TESTS FOR SUGAR IN THE URINE.--The diagnosis of diabetes mellitus, the disease being once suspected, is easy. The passage of large amounts of pale urine of high specific gravity, the presence of thirst, dryness of the mouth, fauces, and skin, and progressive emaciation even while the appetite is good, can scarcely be misinterpreted. In the urine from such a case the application of any of the tests for sugar will produce prompt response. The urine is not always so much increased as to attract attention, while its color is also sometimes but slightly changed; but the symptoms of thirst and dryness or clamminess of the mouth are seldom wanting. On the other hand, the discovery of a glycosuria without these symptoms is, as a rule, accidental. It is a question how far such degrees of glycosuria as do not produce the usual symptoms of diabetes in an appreciable degree are signs of positive disease. At the same time, its detection is important, in that there is always danger of the simple glycosuria becoming a diabetes--a danger which its recognition and suitable treatment may avert. Accordingly, the urine of all persons having unusual appetites without evident cause, {211} and of those who are fond of eating and drinking, should be tested for sugar. This should also be done for those who have passed through severe mental or physical strain, have suffered shock or concussion of the nervous system, blows upon the abdomen, etc.

Testing for Sugar.--Under the head of Diagnosis I prefer to include the testing for sugar, which requires some detailed consideration. Unless it be that the indigo test recently revived by George Oliver of London prove more delicate, that form of cupric test known as Fehling's solution is, with suitable precautions, all things considered, the most satisfactory for general use.

Fehling's volumetric solution, suitable for both qualitative and quantitative purposes, is made as follows: Dissolve 34.639 grams of pure crystallized cupric sulphate in about 200 cubic centimeters of distilled water; 173 grams of chemically pure crystallized neutral sodio-potassic tartrate and 80 grams of potassium hydrate in 500 or 600 c.c. of distilled water. To the latter add the copper solution slowly, and dilute the clear mixed fluid to 1 liter. One cubic centimeter of this solution will be decolorized by 0.005 grm. of sugar, or 200 grains will be decolorized by 1 grain of sugar. Or the copper may be dissolved in 1 liter of water, and the tartrate and potassium hydrate in another, and a cubic centimeter of each mixed at the moment they are to be used.

For qualitative testing, put a cubic centimeter of Fehling's solution into a test-tube (or if the copper and the alkaline sodio-potassium tartrate solutions are kept separate, a cubic centimeter of each), and dilute with distilled water to 5 c.c. Boil, and if, after the lapse of a couple of minutes, the solution remain unchanged, it is fit for testing. If it becomes turbid or a red sediment falls, it is spoiled, and a new solution should be obtained.[38] A cubic centimeter of the suspected urine is then measured out and added drop by drop to the solution kept hot. If there is much sugar, the first drop will throw down a yellow precipitate of suboxide of copper, which becomes rapidly red. If no reaction takes place after adding the entire cubic centimeter of urine, the addition should be continued until 4 c.c. are added, when, if, after the mixture has cooled, there be no response, it may be concluded that the urine is free from sugar. By operating with a cubic centimeter of the test-fluid and the same quantity of urine or multiples thereof, we may roughly estimate the proportion of sugar. Thus, if the cubic centimeter of undiluted urine just decolorizes the cubic centimeter of Fehling's solution, sugar is present in the proportion of one-half of 1 per cent.; or if a half cubic centimeter of the urine removes all the color, the quantity is 1 per cent. If the urine is highly charged with sugar, it may be diluted, and the degree of dilution being remembered, a rough quantitative estimation may be similarly made.

[Footnote 38: Should this not be possible, a little more soda may be added and the fluid filtered, when it is again ready for use.]

If the urine contains very minute quantities of sugar, the reaction is less satisfactory. The copper is reduced, but the suboxide is so small in quantity that it is obscured by the excess of copper solution, and a mixture results which is greenish or greenish-yellow or yellow or milky, and on standing a small yellow sediment falls to the bottom. Now, it dare not be said that it is sugar which produces such reaction. It may be {212} sugar, but it may also be uric acid. Uric acid is really more frequently a source of error than is commonly supposed. I have myself seen the reaction due to it so vivid that I did not suspect it could be due to any reducing agent excepting sugar; but, noting the next day a copious sediment of uric acid which had fallen during the night, a testing of the supernatant fluid then revealed no reaction whatever. Such a urine, after being treated by the lead process to get rid of the uric acid, fails also to respond. But this process is very tedious,[39] and cannot be conveniently carried out by the busy practitioner. The same thing is, however, accomplished by treating the urine with hydrochloric acid, which in twenty-four hours precipitates all of the uric acid. Simple precipitation by lead acetate solution and filtration does not answer, because all of the uric acid is not thus removed. Other substances, as hippuric acid, urates, hypoxanthin, etc., are said to act similarly, but they produce no practical interference with the test. On the other hand, a small amount of sugar may be present and yet fail to show the reaction, because the cuprous oxide is held in solution by certain substances. Such are ammonia and nitrogenous matters, including albumen, creatinin, pepsin, peptones, urinary coloring matters, etc. The latter probably produce their effect through the ammonia which is given off while heating them in the presence of an alkali. Hence all albumen should be precipitated and filtered out of urines suspected to contain sugar, and the heat applied should not be too great. Finally, excess of glucose will also hold in solution cuprous oxide, so that the suspected urine should not be added in too large a quantity at a time, but rather drop by drop.

[Footnote 39: The details of this process will be found in the writer's work on the _Practical Examination of Urine_, 5th ed., 1883, p. 63.]

But qualitative testing is not sufficient during the treatment of a case of diabetes. The percentage of sugar and the quantity discharged in twenty-four hours should be determined occasionally. The process is done as follows: Place 10 cubic centimeters of Fehling's solution in a porcelain capsule, and dilute it with 40 c.c. of distilled water. Fill a Mohr's burette with the urine, which, if it contain more than 1 per cent. of sugar, should be diluted with nine times its bulk of distilled water. Slowly heat the contents of the capsule to boiling, and then allow a little of the diluted urine to run in from the burette; continue the cautious addition of urine and the gentle heating until the blue color is completely removed from the Fehling's solution. To determine the exact moment at which this takes place requires a little experience, but its recognition is facilitated by carefully tilting the capsule after each addition and stirring, so that its clear white surface may be seen through the edge of the fluid and contrasted with the latter. The number of cubic centimeters of urine used should now be read off from the burette, the number of c.c. of undiluted urine calculated therefrom, and each c.c. multiplied by .005 grm. The result indicates the quantity of sugar in grams in the urine employed, whence the percentage of sugar is determined, and also the twenty-four hours' quantity, the amount of urine passed in that period being known.

The Fermentation Test.--A very simple and easy method of determining the proportion of sugar is by Roberts's fermentation method, which, although not so precise as the volumetric process, is still {213} sufficiently so for clinical purposes. A small piece of German yeast or a teaspoonful of liquid yeast is added to about four ounces (120 c.c.) of the urine, which is kept lightly stopped, at a temperature of 20° to 30° C. (68° to 80° F.), for about twelve hours; at the end of this time the sugar will have been converted into alcohol and carbonic acid. The latter will have passed off, and the urine lost in weight because of the destruction of sugar; while the difference between the specific gravity before and after the fermentation indicates the number of grains of sugar per fluidounce. Thus, suppose the specific gravity before fermentation to have been 1040, and afterward 1025; there will have been 15 grains of sugar to the fluidounce, whence, again, the twenty-four hours' quantity can be calculated. If the metric system is used, each degree of specific gravity lost will correspond to .2196 grams of sugar in every 100 c.c. of urine.

The specific gravity of the fermented urine should be compared with that of the urine soon after it is passed, because saccharine urine under suitable circumstances undergoes fermentation without the addition of yeast; and, the specific gravity being thus lowered spontaneously, the reduction in the urine fermented by yeast would appear less than it actually is. At the same time, care should be taken that the urine is of the same temperature when the specific gravity is taken before and after fermentation.

The Picric Acid and Potash Test.--Although attention was called in 1865 by C. D. Braun,[40] a German chemist, to a reaction between grape-sugar and picric acid, as the result of which the latter is converted into picramic acid, very little attention seems to have been paid to this announcement. Quite ignorant of it, George Johnson rediscovered this reaction in 1882, and published it in 1883.[41] It is applicable to both qualitative and quantitative purposes. In order to make use of it, a standard comparison-solution is made as follows: Take 1 fluidrachm of a solution of grape-sugar, 1 grain to the fluidounce; mix it in a long test-tube with half a drachm of liquor potassæ (U. S. P. or B. P.) and ten minims of a saturated solution of picric acid; dilute the mixture to 4 fluidrachms with distilled water, to facilitate which a tube used for the purpose may be marked at 4 fluidrachms. Raise the mixture to the boiling-point, and continue the boiling for sixty seconds, to ensure complete reaction between the sugar and picric acid. During the boiling the pale-yellow color of the liquid is changed to a vivid claret-red. Cool the liquid by cautiously immersing the tube in cold water, and if it is not then at the level of the 4-drachm mark, raise it to this by adding distilled water. The standard color thus obtained is that which results from the decomposition of picric acid by a grain of sugar to the ounce, four times diluted, or by a solution of sugar containing one-quarter of a grain per ounce. But the picramic solution rapidly becomes pale on exposure, so it becomes necessary to make a more permanent solution to use as a standard. This may be accomplished by combining liquor ferri perchloridi drachm j, liquor ammonii acetatis drachms iv, acidum aceticum (glacial) drachms iv, and water enough to make ounces iiss. The color of this is identical with that of the picric acid reduced by a one-grain solution diluted four times, and, {214} according to Johnson, it will retain its color unchanged for at least six months. At the same time, whenever a new solution is made it should be compared with that of the one-quarter grain per ounce solution of sugar, boiled with picric acid and potash.

[Footnote 40: "Ueber die Umwandlung der Pikrinsaüre in Pikramminsaüre, und Ueber die Nachweisung der Traubenzucker," _Zeitschrift für Chemie_, 1865.]

[Footnote 41: _British Medical Journal_, March, 1883.]

For qualitative testing Johnson directs: To a drachm of urine in a test-tube add a few drops, enough to give a distinct yellow color, of a saturated solution of picric acid. Add about 10 drops of liquor potassæ and boil. If sugar is present, the mixture becomes promptly red in hue.

The shading of the side tube indicates the ferric-acetate standard. The darker shading at the bottom of the graduated tube shows the saccharine fluid, darkened by boiling with picric acid and potash, and occupying ten divisions between dilution.]

The quantitative estimation is based upon an accurate approximation, by dilution, of the color of the tested fluid with that of the standard solution. Johnson recommends the picro-saccharimeter figured in the text. This is a stoppered tube twelve inches long and three-quarters of an inch in diameter, graduated into ten, and each of these again into ten other equal divisions. By the side of this tube, and held in position by an S-shaped band of metal, is a stoppered tube of equal diameter and about six inches long, containing the standard solution corresponding to the reaction of the one grain of grape-sugar with picric acid and potash diluted four times.

It has been found that ten minims of a cold saturated solution of picric acid are rather more than sufficient for decomposition by one drachm of a solution of grape-sugar in the proportion of one grain to the ounce. A drachm of the solution will therefore contain one-eighth of a grain of sugar, which is the strength of the solution used in making the standard-color liquid. In making the analysis, while the quantity of liquor potassæ used is always the same and the dilution is always to four drachms, the picric acid must be added in proportion to the amount of sugar present, so that if the urine contains as much as six grains to the fluidounce, sixty drops or a fluidrachm of the picric-acid solution would have to be used; and when the proportion of sugar is higher than this, the urine should be diluted with distilled water five or ten times before commencing the analysis, and the degree of dilution remembered in the computation.

If, now, a drachm of a solution of grape-sugar, containing two grains to the ounce, be mixed with the same quantity of liquor potassæ and picric acid and increased by the addition of distilled water to four drachms in the boiling tube, and boiled as before for sixty seconds, the result will be a mixture of much darker color than will be produced by the one-grain solution; but if the dark liquid be diluted with its own volume of water, the color will be the same as that of the one-grain solution or the standard.

It is plain, then, that if a given quantity of the dark saccharine fluid produced by boiling--say, enough to cover ten divisions of the graduated tube, as shown in the figure--has to have added to it an equal bulk of distilled water in order to produce {215} the color of the standard solution, the tested fluid will be of the strength of two grains to the ounce; if three times, three grains; and so on; while fractional additions, as indicated by the graduated markings, would show fractional additions to the proportion of sugar.[42]

[Footnote 42: A more exact comparison of the saccharine liquid with the standard is made by pouring into a flat-bottomed colorless tube six inches long and an inch in diameter as much of the standard solution as will form a column about an inch in height, and an exactly equal column of the saccharine fluid in a precisely similar tube. The operator then looks down through the two tubes at once, one being held in each hand, upon the surface of a white porcelain slab or piece of white paper. In this way slight differences of tint are easily recognized; and if the liquid to be analyzed is found darker than the standard, it is returned to the graduated tube and diluted until the two liquids are found to be identical in color, when the final reading is made.]

The presence of albumen, even in considerable amount, has but little effect upon the test, nor does the coloring matter of normal urine, according to Johnson; but he says there is a coloring matter associated with ser-albumen in albuminous urine, and with egg-albumen as well, which has a reducing action on picric acid. This is partly separated by filtering off the precipitated albumen, and entirely removed by repeated filtration through animal charcoal. So, too, the albumen removed by coagulation and filtration, if thoroughly washed, does not give any red reaction if boiled with picric acid and potash diluted in the same proportion as when testing for sugar. Neither do any other unoxidized sulphur compounds found in urine decompose the picric acid and render the test fallacious.

Johnson and his son, G. Stillingfleet Johnson, claim that the picric-acid test is as accurate as any other, and that it is even more accurate than either Fehling's or Pavy's process, because the picric acid is not acted upon by uric acid or urates, which do reduce the oxide of copper. The method of analysis by the picro-saccharimeter, they claim, is at least as speedy and as easy as any other. The materials and apparatus required are easily prepared, inexpensive, and not, like Fehling's copper solution, liable to undergo rapid changes.

But while Johnson claims that neither coloring matters of normal urine nor uric acid reduce the picric acid, he admits that he has tested with picric acid and potash a large number of specimens of normal urine with the almost uniform result of a depth of color indicating the proportion of .6 of a grain of sugar to the fluidounce, the indication varying between the limits of .5 to .7 grain. The ammonio-cupric method used at the same time gave results of from .7 to .9 grain to the fluidounce, or an excess of .1 to .3 grain. Now, if my own views, the grounds for which are announced elsewhere,[43] are correct, strictly normal urine contains no sugar, and any reducing action upon oxide of copper is due to uric acid, either picric acid is reduced to a degree by uric acid or by some other constituent of normal urine. This, in the light of Oliver's[44] recent investigations, may be kreatinin. For he has shown that kreatinin strikes in a few seconds a red color with the cold alkaline picric solution, which is quickened by heat. From this it would seem that the exact value of the picric-acid test has as yet to be determined.

[Footnote 43: Tyson, _Practical Examination of Urine_, 4th ed., Philadelphia, 1884.]

[Footnote 44: _On Bedside Urine-Testing, including Qualitative Albumen and Sugar_, by Geo. Oliver, M.D., London, Member of the Royal College of Physicians of Lond., etc., 2d ed., London, 1884.]

{216} The Indigo-Carmine Test.--The fact that indigotine, the coloring matter of commercial indigo, is converted into indigo when heated with an alkali in the presence of glucose and certain carbohydrates, has recently been applied by George Oliver of London in the construction of a test-paper. Carmine of indigo is the sulph-indigotate of sodium, an intensely blue salt, soluble in 120 parts of water. Sulph-indigotic acid is made by heating indigo with sulphuric acid, and when combined with a base, sodium, produces indigo-carmine. When sodium carbonate is mixed with a solution of indigo-carmine, the latter is precipitated in a minute state of division, but is redissolved on heating, when there results a greenish-blue solution. A freshly-made mixture of the indigo solution and sodium carbonate furnishes a fluid not unlike Fehling's solution, which gives the reaction to be described with glucose. Unfortunately, such a mixture will not keep, and the reagent would be useless but for the happy idea of Oliver of making the test-paper. In doing this bibulous paper is immersed in a solution of indigo-carmine with carbonate of sodium.[45] The paper is then cut into strips an inch long and one-quarter of an inch wide.

[Footnote 45: No more precise directions than this are given by Oliver, either in his papers in the _Lancet_ for 1883 or in his little book just published, _On Bedside Urine-Testing_. The sugar test-papers, as well as the entire series of albumen test-papers, suggested by Oliver, are now made by Parke, Davis & Co. of New York, and by Wilson & Son, Harrogate, London.]

Mode of Testing.--One of the test-papers and a sodium carbonate paper[46] are dropped into a half-inch test-tube, and water added until the upper end is just covered; a column of fluid one inch in height and half an inch in diameter will thus be produced, so that the solution of carmine obtained on boiling will always acquire the same concentration. Heat is now applied, the tube being gently shaken, and boiling kept up for a second or two. A beautiful blue solution will result. The test-paper may now be removed or allowed to remain.

[Footnote 46: Test-papers of the same size, charged with a saturated solution of sodium carbonate.]

Not more than one drop of the suspected urine is let fall into the tube from a pipette held in an upright position. Drops of equal size are thus secured. The contents of the tube are again freely boiled for a few seconds, after which the tube should be raised an inch or more from the flame and held without shaking, while the solution is kept quite hot, but not boiling, for exactly one minute. If glucose be present in abnormal amount, the soft rich blue will be seen first of all to darken into violet; then, according to the quantity of sugar, there will appear in succession, purple, red, reddish-yellow, and finally straw-yellow. When the last-named color has been developed the slightest shaking of the tube will cause red streaks to fall from the surface and mingle with the pale yellowness of the solution, while further agitation will cause the return of purple and violet and the restoration of the original blue.

The time required for the commencement of the reaction after the boiling of the test liquid is in inverse proportion to the amount of glucose present. When the latter is large, over 20 grains to the ounce, it will be but a few seconds; but when small, 2 or 3 grains, from thirty to sixty seconds may elapse. If the urine do not contain more than the normal amount of sugar[47]--_i.e._ under half a grain to the ounce--the color of the solution {217} at the end of the heating for one minute will be unchanged. The test is available by artificial light as well as by daylight.

[Footnote 47: It will be noted from this that Oliver accepts the view that there is a small amount of sugar in normal urine.]

Precautions.--1. Care should be taken during the testing not to shake the tube or to permit free ebullition. 2. While keeping the contents of the tube hot, the latter should not be held up between the eye and the sky, for then the early color-changes will probably escape observation. The tube should be kept below the eye-level and its contents viewed by the reflected light of some bright object, such as a sheet of white paper propped up an inch or two beyond the tube as a background. 3. Oliver is not aware that the presence of earthy carbonates will prevent the carmine reaction, but as a precautionary measure he suggests the use of a soda-paper whenever the water is exceptionally hard. 4. The acids of the urine rob the carmine-paper of much alkali, so that the addition of more than a certain number of drops of urine--varying of course with the degree of acidity--will at first retard and then prevent the reaction. The addition of the soda-paper will prevent any such interference, although Oliver says that by invariably submitting only one drop of saccharine urine to the test-paper, and keeping up the heating for not less than two minutes, he has never failed to obtain the characteristic reaction without using a soda-paper. It is well to remember, however, that an excessively acid urine may thus interfere, and that the soda-paper will prevent it. 5. The blue color of the carmine is discharged by caustic alkali--liquor potassæ or sodæ. The only chance of being misled by this reaction lies in using an imperfectly cleansed test-tube which may have contained Fehling's solution or the alkaline picric solution. The caustic alkali converts the blue carmine into a green solution, which, on heating, disappears; nor does it return by again shaking the contents of the tube.

Critical comparison of this test with Fehling's solution and picric acid by Oliver has shown that of sixty-four substances experimented upon, normal and abnormal constituents of urine or medicines which after ingestion are eliminated in the urine, Fehling's was reduced by fifteen, picric acid by eleven, and indigo-carmine by eight. The only substances producing the characteristic play of colors with indigo-carmine test-papers reacted with both picric acid and Fehling's solution. They were unoxidized phosphorus, ammonium sulphide, milk-sugar, dextrin, inosit, gallic acid, tannic acid, and iron sulphate. Both the carmine and picric acid were reduced by inosit, which merely turned Fehling's solution green. On the other hand, uric acid and urates, which reduce Fehling's solution, do not react with the carmine test, while kreatinin, which reacts with picric acid also, does not respond to the carmine. Albumen, if abundant, interferes with Fehling, but not with the indigo-carmine.

Detection of Inosit.--It has been said that inosit sometimes accompanies, and even substitutes, grape-sugar in the course of diabetes. It has been mentioned that it does not reduce Fehling's solution, but turns it olive-green. It reduces the carmine and alkaline picric acid solution, and is therefore not recognizable by these. The methods recommended for its recognition in the books are troublesome, and as its presence in the absence of sugar indicates a favorable change, it is not likely that a more precise recognition than is furnished by the olive-green reaction will be needed for clinical purposes.

PROGNOSIS.--The prognosis in diabetes depends upon the organ whose {218} involvement is responsible for the symptoms, upon the stage at which the condition comes under observation, and upon the age of the patient. It has appeared to me that the cases of diabetes depending upon pancreatic disease are the most intractable, that their progress is scarcely checked by treatment, and that they are comparatively rapidly fatal in their termination. In the others, where the symptom is one of a central nervous lesion, it has always seemed to me to be of secondary importance that the glycosuria is itself less marked, that it is unattended by the other distinctive symptoms of diabetes, and that its issue is that of the nervous malady.

Again, it is well known that the later in life diabetes occurs the more amenable it is to treatment, and that if a proper diabetic diet be adhered to by the patient his life need scarcely be shortened. On the other hand, diabetes mellitus is a disease in which the expectant plan is dangerous. If it does not improve it usually gets worse; and many a patient has fallen a victim to his own indifference and indisposition to adhere to a regimen under which he could have lived his natural term of life. This is especially the case when the disease appears after middle life.

If, on the other hand, the condition becomes thoroughly established before twenty-five years of age, it is less amenable to treatment; but even in such cases a promptly vigorous treatment is sometimes followed by recovery. I have already mentioned the case of a child twelve years old in which complete recovery took place.

If tubercular phthisis supervenes, recovery is not to be expected, while intercurrent disease, as pneumonia, which is rather prone to occur, is very much more serious and apt to terminate fatally.

TREATMENT.--The treatment of the aggregate of symptoms known as diabetes mellitus is conveniently divided into the dietetic, the medicinal, and the hygienic, of which the first is by far the most important. The efficiency of this treatment depends upon the successful elimination from the diet of all articles containing grape-sugar, cane-sugar, beetroot-sugar, and starch, it being universally recognized that in the early stages of the disease these foods are the sole source of the glucose in the urine. The normal assimilative action of the liver, by which the carbohydrates are first stored up as glycogen, and then gradually given out as glucose or maltose to be oxidized, being deranged, such foods not only become useless as aliments, but if continued seem to aggravate the glycosuria, and the excretion of sugar steadily increases. There is, therefore, a double reason for excluding them from the food. This is easiest accomplished by an exclusive milk diet. The exclusive milk treatment of diabetes was suggested by A. Scott Donkin in 1868. That he is correct in his assertion that in the early stages of diabetes lactin or sugar of milk is quite assimilable, and does not in the slightest degree contribute to the production of glycosuria, I cannot doubt; that it is in this respect even superior to casein, as claimed by Donkin, I am not prepared to state from actual knowledge; but that casein itself resists the sugar-forming progress immeasurably greater than any other albuminous substance, so that in all but the most sure and advanced or complicated cases its arrest is complete, I am also satisfied. Certain it is that in a large number of diabetics the use of a pure skim-milk regimen results in a total disappearance of the sugar from the urine. That in a certain proportion of these cases a {219} gradual substitution of the articles of a mixed diet may be resumed without a return of the symptoms is also true. In other more confirmed cases the use of skim-milk results in a decided reduction in the amount of sugar, with an abatement of other symptoms, which continues as long as the diet is rigidly observed. In still other cases, while the skim-milk treatment makes a decided impression upon the quantity of sugar, it still remains present in considerable amount, while the disease progresses gradually to an unfavorable issue. These three classes of cases represent, ordinarily, different stages of the disease, so that it may be said that as a rule cases recognized sufficiently early may be successfully treated with skim-milk, although it may occasionally happen that cases pursue a downward course from the very beginning despite all treatment. Yet I have never seen a case which, when taken in hand when a few grains of sugar only to the ounce were present, failed to yield to this treatment.

As to the method of administration, my practice with adults is to give eight ounces (an ordinary tumblerful) every two hours, beginning at seven or eight o'clock in the morning, and continuing to the same hour in the evening. Sometimes it is well to begin with half as much at first, but rapidly to increase to the required amount. This method ensures the ingestion of three to four quarts daily--a quantity generally sufficient to maintain the body-weight of an adult person of average size and taking moderate exercise, although a slight reduction may take place at first. But if the individual is very active or of large size, it will not be found sufficient. In such event the quantity must be increased as demanded by a feeling of unsatisfied hunger. I have known fourteen pints to be taken in twenty-four hours. But when the quantity becomes thus large, the inconvenience in ingesting it is very great, and it is much more convenient to coagulate the casein of a part of the milk and use the curd thus obtained, while the second part is drunk. Curd may be seasoned with salt to make it more palatable, and should be thoroughly masticated before it is swallowed.

The milk should not be taken too cold, especially if the amount ingested is large, else it is likely to reduce the temperature of the stomach below the point necessary for gastric digestion. The temperature should not be less than 60° F., nor much over 100°. Something depends upon the idiosyncrasies of the patient, which must be the guide as to temperatures intermediate between those named.

The chief advantage of the skim-milk over the unskimmed is simply that it is more easy of digestion. Many persons who cannot take unskimmed milk for any length of time without its deranging the digestion, or, as is commonly said, making them bilious, can take with impunity milk from which the cream is removed. Although Salomon[48] claims to have shown that glycogen is produced in the liver of rabbits fed upon pure olive oil, it is at least probable that fat is among the last of the substances undergoing this conversion, and in ordinary cases of diabetes it is rather its indigestible nature which renders it prudent to remove from milk the greater proportion of fat by skimming it off.

[Footnote 48: _Virchow's Archiv_, Bd. 61, Heft 3, 1874, 18.]

Still more easily assimilable is the peptonized milk, in which the casein is at least partially digested, and it should be employed where there is any {220} difficulty in the way of using the ordinary milks. Either skimmed or unskimmed milk may be used for peptonizing, the latter peptonized being quite as easy of digestion as the former unpeptonized. I have found the extractum pancreatis of Fairchild Brothers & Foster most successful in the peptonizing of milk, and according to the following directions: Into a clean quart bottle put 5 grains of extractum pancreatis, 15 of bicarbonate of sodium, and a gill of cool water; shake, and add a pint of fresh cool milk. Place the bottle in a pitcher of hot water or set the bottle aside in a warm place, usually for three-quarters of an hour. When the milk has acquired a slightly bitter taste, it has been completely peptonized--that is, the casein has been completely converted into peptone. After the process is complete the milk must be immediately put on ice.

It is not always necessary to completely peptonize the milk, and if the bitter taste is unpleasant the process may be stopped short of this by putting the milk on ice, the degree of digestion depending upon the length of time the milk is kept warm.

While I am confident that the promptest and most effectual method of eliminating sugar from the urine is by a milk diet, it occasionally happens that a patient cannot or will not submit to so strict a regimen. In other instances, again, it is not necessary to resort to it, because a less restricted diet answers every purpose.

A suitable diabetic diet would also be obtained by eliminating from the bill of fare all saccharine and amylaceous and other sugar-producing substances. Such a diet is, strictly speaking, impossible. For, apart from the fact just mentioned that even fats, as well as albuminous substances to a degree, are capable of producing glycogen, the monotony of a pure meat diet soon becomes unbearable, to say nothing of other derangements it may produce. Fortunately, it is not necessary that such an exclusive diet should be maintained, for certain saccharine foods seem capable of resisting the conversion into sugar more than others. Sugar of milk, or lactin, has already been mentioned as one of these, and to it may be added the sugar of some fruits, and probably also inosit or muscle-sugar, mannite or sugar of manna, and inulin, a starchy principle abundant in Iceland moss. It is found also that there are many vegetable substances containing small quantities of sugar and sugar-producing principles which may be used with impunity in at least the milder forms of diabetes. This being the case, a bill of fare for diabetics may be constructed quite liberal enough to satisfy the palate of most reasonable persons by whom it is attainable.

FOOD AND DRINK ADMISSIBLE.--Shell-fish.--Oysters and clams, raw and cooked in any way, without the addition of flour.

Fish of all kinds, fresh or salted, including lobsters, crabs, sardines, and other fish in oil.

Meats of every variety except livers, including beef, mutton, chipped dried beef, tripe, ham, tongue, bacon, and sausages; also poultry and game of all kinds, with which, however, sweetened jellies and sauces should not be used.

Soup.--All made without flour, rice, vermicelli, or other starchy substances, or without the vegetables named below as inadmissible. Animal soups not thickened with flour, beef-tea, and broths.

Vegetables.--Cabbage, cauliflower, brussels-sprouts, broccoli, green {221} string-beans, the green ends of asparagus, spinach, dandelion, mushrooms, lettuce, endive, coldslaw, olives, cucumbers fresh or pickled, radishes, young onions, water-cresses, mustard and cress, turnip-tops, celery-tops, or any other green vegetables.

Fruits.--Cranberries, plums, cherries, gooseberries, red currants, strawberries, apples, without sugar. Or they may be stewed with the addition of bicarbonate of sodium instead of sugar. (See below.)

Bread and cakes made of gluten, bran, or almond flour, or inulin, with or without eggs and butter. Griddle-cakes, pancakes, biscuit, porridges, etc. made of these flours. Where especial stringency is required these should be altogether omitted.

Eggs in any quantity and prepared in all possible ways, without sugar or ordinary flours.

Nuts.--All except chestnuts, including almonds, walnuts, Brazil-nuts, hazel-nuts, filberts, pecan-nuts, butternuts, cocoanuts.

Condiments.--Salt, vinegar, and pepper in moderate quantities.

Jellies.--None except those unsweetened. They may be made of calf's-foot or gelatin and flavored with wine.

Drinks.--Coffee, tea, and cocoa-nibs, with milk or cream, but without sugar; also milk, cream, soda- (carbonated) water, and all mineral waters freely; acid wines, including claret, Rhine, and still Moselle wines, very dry sherry; unsweetened brandy, whiskey, and gin. No malt liquors, except those ales and beers which have been long bottled, and in which the sugar has all been converted into carbonic acid and alcohol.

Vegetables to be especially Avoided.--Potatoes, white and sweet, rice, beets, carrots, turnips, parsnips, peas, and beans; all vegetables containing starch or sugar in any quantity.

The following list, including essentially the same articles, but arranged in the shape of a true bill of fare, by Austin Flint, Jr.,[49] will be found very convenient: