It is evident that an agency involving any part of this tract in such a way as to paralyze the vaso-motor nerves of the liver is capable of producing glycosuria. Such cause may operate upon the central ganglia whence the nerves emanate, as the vicinity of the oblongata and upper parts of the spinal cord or the coeliac ganglion and its branches, including those to the pancreas. Or the irritation may be peripheral and its effects reflex. We have seen that irritation of the central end of the cut vagus will produce glycosuria. Any irritation, therefore, involving the peripheral distribution of this nerve may produce it. Hence embarrassed respiration, whether due to disease of the respiratory passages, strangulation, or inhalation of irrespirable gases and anæsthetics, produces glycosuria in dogs and rabbits; and this symptom has been known to attend these conditions in the human subject. So, too, glycosuria may be produced by such substances as woorara, strychnia, morphia, and phosphoric acid, introduced into the blood and irritating the terminal filaments of the pneumogastrics, or it may be brought about secondarily through the embarrassed respiration these drugs produce. Such peripheral irritation may reside also in the stomach, intestines, liver, or any organ to which the pneumogastric is distributed.

It is not unlikely that irritation of the extremities of sensory nerves other than the pneumogastric may become the cause of reflex glycosuria. Even puncture of the floor of the fourth ventricle itself may be reflex in its operation, the roots of the pneumogastric being thus irritated. The effect of the irritation conveyed to the glycogenic centre is to inhibit the usual tonic influence of the vaso-motor nerve upon the vessel walls. Among the experimental irritations, in addition to puncture of the floor of the fourth ventricle, which produce glycosuria by reflex action, are injuries of the cerebral lobes and cerebellum, optic thalami, cerebral peduncles, pons varolii, middle cerebellar peduncles, and even of the sciatic nerve and brachial plexus; whence it may be inferred that pathological irritation in the same situations may result in a glycosuria, which is temporary or permanent according as the irritation is temporary or permanent.

Finally, there is no reason why an inhibitory reflex action should not originate in the sympathetic itself. When we remember that this nerve is both sensory and motor in function, and that the inhibitory influence to which the heart's action is subject is accomplished through the sympathetic as a sensory nerve and the pneumogastric as a motor, there is no reason why similar results may not be brought about by the sympathetic alone. This being the case, we need not ascribe glycogenic phenomena to irritation in Eckhard's sense—that is, to a direct stimulant action of the irritant upon the vaso-motor nerves of the liver—but may suppose a sensory influence to ascend one set of sympathetic filaments and an inhibitory influence to descend through another.

Dr. Pavy has recently put forward some chemical theories which explain the action of the hyperæmia in producing glycosuria, but they do not account for the hyperæmia itself. In healthy digestion the carbohydrates (starch and sugar) are converted, not into glucose, but into maltose, C₁₂H₂₂O₁₁, dextrin being intermediate in composition. Maltose is absorbed and assimilated, converted into glycogen. So, too, when glucose is ingested as such, it is converted by the glucose ferment into maltose in the stomach and intestines. For the proper production of maltose and its assimilation a good venous blood, producing a maltose-forming ferment, is necessary. In diabetes, in consequence of the dilatation of the arteries of the chylopoëtic viscera, the blood enters the liver too little deoxygenated, and a glucose-forming ferment is produced. The glucose thus formed is not assimilable, but passes off into the circulation and the urine.

MORBID ANATOMY.—Such are some of the facts bearing upon the pathology of diabetes mellitus. Throwing out the milder type of cases, in which glycosuria is the result of an over-ingestion of saccharine and sugar-producing food—and these can scarcely be called instances of essential diabetes—it is evident that glycosuria may be produced in a variety of ways operating through the nervous system; and accordingly we may infer that there is scarcely an organ in close relation with the sympathetic system derangement of which is not capable of producing it. Among these we would naturally expect to find conspicuous alterations in the nervous centres, and yet I have never found changes in these centres after death. At the same time, others have noted meningitis, tubercular and traumatic, apoplectic effusions, and tumors of the brain, especially in the neighborhood of the medulla oblongata. The alterations in the nerve-centres described by Dickinson as the essential morbid anatomy of diabetes I have looked for in vain. These changes are described as a cribriform or porous condition of the white nervous matter, said to be visible to the naked eye. The spaces thus produced are partially occupied by dilated blood-vessels, which, in turn, are surrounded by dilated perivascular sheaths and broken-down nervous matter, into which extravasations of blood have taken place, as evidenced by the presence of pigment-granules. The changes are found in the white matter of the convolutions of the brain, but fewer and larger in the central portions. The corpora striata, optic thalami, pons, medulla, and cerebellum are favorite seats for the largest and most striking holes. In rapidly-fatal cases the cavities are sometimes filled with a translucent, gelatinous substance, containing, besides vascular elements, the globular products of nervous disintegration. In the more chronic forms of the disease, as it occurs in elderly persons, the excavations are usually empty, although the elements of nervous decay are still to be found fringing the margins or collected as an irregular sheath upon the dilated or shrunken artery. There are changes in the cord similar to those in the brain, but less decided. But the most striking alteration in the cord, according to Dickinson, although not always present, is dilatation of the central canal, which in the dorsal and lumbar regions is sometimes expanded to many times its normal diameter, and forms a conspicuous object immediately after the cord is divided.

These alterations have eluded the vigilance of other pathologists who have sought for them in well-determined cases of diabetes mellitus, while they have been found, on the other hand, in the nervous centres when no diabetes was present. In the recent discussion on diabetes at the Pathological Society of London, Douglas Powell⁷ seemed to be the only one who was convinced that most of Dickinson's specimens were examples of positive lesions.

⁷ London Lancet, May 5, 1883, p. 776.

A hyaloid thickening of the blood-vessels of the brain has been noted by Stephen Mackenzie⁸ and Seymour Taylor⁹ in some cases, and miliary aneurisms of the retina in one.

⁸ Discussion on Diabetes, Path. Soc. of London, London Lancet, April 7, 1883, p. 593.

⁹ Ibid., Lancet, May 5, 1883, p. 774.

Of other organs, one of the most frequently found diseased is the pancreas, and, according to Senator, it is fair to assume that disease of the pancreas is present in about one-half of all cases of diabetes. As the result of increased experience, I am inclined to attach much more importance to pancreatic disease as a cause of diabetes than I did a few years ago. Among the changes found is a pseudo-hypertrophy, which consists chiefly in a hyperplasia of the connective tissue, fatty degeneration of the gland-cells, and atrophy of the glandular structure; cancerous disease; calculous concretions in the ducts with or without obstruction; and cystic dilatation.

Facts bearing upon the relation of pancreatic disease to diabetes have been accumulating since Cowley first discovered calculi in the pancreas of a diabetic, and Bright pancreatic cancer in a similar case. Since then instances have multiplied to such extent that it would be unprofitable to enumerate them. But in 1877, Lancereaux¹⁰ communicated to the French Academy of Medicine specimens of profound lesion of the pancreas from cases dying of diabetes mellitus. This, he alleged, constitutes a special and distinctive variety of diabetes, characterized by sudden onset, emaciation, polydipsia, polyphagia, and peculiar alvine dejections. More recently, Depierre¹¹ has confirmed these observations, apparently establishing this variety of diabetes mellitus, of which a very rapid course—six months to three years—and the habitual presence of diarrhoea are characteristic; while the presence of greasy or creamy stools, and the appearance in them of undigested nitrogenous substances, may aid in the diagnosis. Precisely such a case, running the same rapid course—less than one year—with emaciation, uncontrollable diarrhoea, creamy stools, jaundice, and pancreatic disease, came under the writer's care in 1882. At the autopsy the pancreas was found enlarged, and numerous gritty particles were disseminated through it.

¹⁰ "Notes et réflexions à propos de deux cas de diabète sucre avec altération du pancréas," Bull. Acad. de Méd., Paris, 1877, 2d Serie, vi. 1215-1240.

¹¹ Med. News and Abstract, vol. xxxix., June, 1881, p. 344, from Jour. de Méd. et de Chir. pratiques, Dec, 1880.

Supposing such pancreatic disease to be primary, it is evident that it must operate through the coeliac plexus, which, with its ganglion, is gradually encroached upon. On the other hand, it is also possible that the disease of the coeliac plexus may be primary, and the coexisting pancreatic disease and diabetes mellitus both secondarily dependent upon it. This can only be settled by more careful study of the coeliac plexus after death from diabetes, but up to the present time facts would seem to support the view of primary pancreatic disease.

The liver is frequently enlarged—sometimes but slightly, at others decidedly. It has been known to reach three times the size of the normal organ. Again, it may be darker and harder—hyperæmic. By minute examination the acini are found enlarged, the capillaries dilated and distended; the liver-cells are enlarged, distinctly nucleated, rounded, and indistinct as to their outline, appearing to fuse into each other. A weak solution of iodine strikes a wine-red color, which, according to Rindfleisch, is confined to the nucleus, but, according to Senator, may extend to the whole cell. This reaction Klebs ascribes to post-mortem changes in the glycogenic substance. They are more striking in the portal or peripheral zone of the lobule, while the intermediate or hepatic artery zone is often fatty, and the central part, surrounded by the rootlets of the hepatic vein, is nearly normal. Stockvis and Frerichs ascribe the enlargement of the liver partially to a new formation of liver-cells—in other words, to a true hypertrophy. At other times the organ has been found reduced in size.

Dickinson, Trousseau, and Budd describe an overgrowth of connective tissue, as well as of the cells of the liver, producing a hypertrophic cirrhosis.

According to Beale, Frerichs, and Folwarczny, the fat which is found in small proportion in the liver-cells in health is often diminished, and even absent, and quantitative¹² analysis by the last-named observer confirms this view. Such diminution may be the forerunner of an atrophy of liver-cells which has been noted, and which, as the disease continues, leads to the atrophy referred to as occasionally present. On the other hand, intense fatty degeneration of the entire organ, similar to that found in phosphorus-poisoning, has been met by Gamgee, associated with a lipæmic state of the blood and symptoms of acute acetonæmia.

¹² Folwarczny, "Leberanalysen bei Diabetes Mellitus," Wiener Zeitschr., N. F., 1859, ii. 6.

The kidneys, in cases which have continued some time, are apt to be hyperæmic and enlarged, although primarily they are uninvolved. It would seem that the long-continued hyperæmia which is a necessary condition of the copious secretion of urine, results, sooner or later, in an over-nutrition of the renal epithelium, a widening of the tubules, and consequent enlargement of the whole organ. The changes are mainly of a parenchymatous or catarrhal rather than an interstitial nature, the epithelium being disposed to shed. These changes may reach a more advanced stage of cellular degeneration, and may be attended by albuminuria. The cells may become very large, present a yellowish-brown color, their nuclei indistinct and non-responsive to ordinary staining solutions, but may take a red stain with a weak solution of iodine, similar to that described in the case of the liver-cells. Mackenzie describes a hyaline degeneration of the intima of the arterioles and a skeleton condition of the epithelium of the collecting tubes.¹³ There may also be a catarrh of the pelves of the kidneys and ureters, due to irritation of the saccharine urine.

¹³ Loc. cit.

Atrophy of the testes has been noted by Romberg and Seegen in young men, and recently Hofmeier¹⁴ has reported the case of a young diabetic woman, aged twenty, who came under observation for pruritus vulvæ, in whom the uterus was found small, scarcely 5 cm. (2 inches) long, and the ovaries very much atrophied. As this young woman had no other ailment, the atrophy was ascribed to the diabetes.

¹⁴ Berliner klin. Wochenschr., 1883, No. 42.

Among the most constant secondary lesions is the aggregate of changes known as those of pulmonary phthisis. But a few years ago, when our ideas on this subject were more definite than they are to-day, and when it was thought we had three distinct varieties of phthisis—the tubercular, the catarrhal, and the fibroid—the phthisis of diabetes was regarded as typically catarrhal.¹⁵ At the present time, however, when the tendency at least is to regard all phthisis as tubercular, diabetic phthisis must be consigned to the same category. At the same time, if the tubercle bacillus is to be regarded as the essential criterion of tuberculosis, it must be stated that the diabetic patient is subject to two different lung processes—at least if the observations of Riegel of Giessen¹⁶ are to be regarded as correct. In two cases of diabetic phthisis studied at his clinic, the sputum of one contained numerous bacilli, while the other, although the case presented the most distinct signs of infiltration of the apex, and although more than fifty preparations were investigated, revealed none. The sputum was also said to present some unusual physical characters. So far as I know, no autopsies of cases showing these clinical differences have been reported, although there have been found in diabetes, distinct from the usual cheesy foci, fibroid changes with small smooth-walled cavities. In such cases tubercle bacilli would be absent, while the physical signs of consolidation would be present.

¹⁵ See the writer's work on Bright's Disease and Diabetes, Philada., 1881, p. 256.

¹⁶ Medical News, Philada., May 19, 1883, from Centralblatt f. klin. Med., Mar. 31, 1883.

As a part of the phthisical process in diabetes, cavities of various sizes are found and gangrene of the lungs has been observed.

ETIOLOGY.—The problem of the etiology of diabetes mellitus is as unsatisfactorily solved as is that of its pathogenesis. Certainly, a majority of cases of diabetes cannot be accounted for. A certain number may be ascribed to nervous shock, emotion, or mental anxiety; a few to overwork; some to injury and disease of the nervous system; others to abuses in eating and drinking. Among the injuries said to have caused diabetes are blows upon the skull and concussions communicated to the brain, spinal cord, or vaso-motor centres through other parts of the body. Hereditation is held responsible for a certain number of cases. Malarial and continued fevers, gout, rheumatism, cold, and sexual indulgence have all been charged with producing diabetes.

Diabetes mellitus is most common in adult life, although Dickinson reports a case at six years which was fatal, Bence Jones a case aged three and a half, and Roberts another three years old; and in the reports of the Registrar-General of England for the years 1851-60 ten deaths under the age of one and thirty-two under the age of three are included. This statement, in view of the experience of the difficulties of diagnosis in children so young, seems almost incredible. I have never myself met a case in a child under twelve years. At this age I have known two, of which one, a boy, passed from under my notice, while the second, a girl, recovered completely. The disease is most common between the ages of thirty and sixty. The oldest patient I have ever had died of the disease at seventy-two years, having been under my observation for three and a half years.

It is decidedly more frequent in men than in women, carefully prepared statistics of deaths in Philadelphia during the eleven years from 1870 to 1880, inclusive, giving a total of 206 deaths, of which 124, or three-fifths, were males, and 82, or two-fifths, females. This is the experience of all.

My own experience has been singular and interesting. Up to April, 1881, I had never met a case in a woman. Of 18 cases outside of hospital practice which I have noted since that date, 9 were men and 9 women. But I still do not recall an instance of a woman in hospital practice, although I have constantly cases among men.

Not much that is accurate can be said of the geographical distribution of the disease. It seems to be more common in England and Scotland than in this country, at least if the statistics of New York and Philadelphia are considered. In the former city, statistics extending over three and a fourth years show that out of 1379 deaths, 1 was caused by diabetes; in Philadelphia, in eleven years, 1 out of 875; in England and Wales, according to Dickinson from observations extending over ten years, 1 out of 632; and in Scotland, 1 out of 916. According to the same authority, the disease is more prevalent in the agricultural counties of England, and of these the cooler ones, Norfolk, Suffolk, Berkshire, and Huntingdon. According to Senator, it is more common in Normandy in France; rare, statistically, in Holland, Russia, Brazil, and the West Indies, while it is common in India, especially in Ceylon, and relatively very frequent in modern times in Wurtemberg and Thuringia. Seegen says it is more frequent among Jews than among Christians, but I have never seen a case in a Hebrew.

SYMPTOMS, COURSE, AND DURATION.—The earliest symptom commonly noted by the diabetic is a frequency of micturition and the passage of larger amounts of urine than is natural. Coincident with or immediately succeeding this is an undue thirst and dryness of the mouth, which soon becomes the most annoying symptom the patient has, the freest draughts of water giving but partial or temporary relief. To this succeeds dryness, and sometimes itching, of the skin and absence of perspiration. A good appetite with fair digestion accompanies this stage of the disease, but notwithstanding this the patient loses in weight. If a male, his attention is sometimes called to his urine by the white spot left after the evaporation of a drop of urine on his boot or clothing or by the stiffness of his linen due to the same cause. To these symptoms are sometimes added an intolerable itching of the end of the urethra in males and of the vulva in females, probably due to the irritation caused by the saccharine urine in passing over and drying upon these parts.

As the disease progresses muscular weakness supervenes. This, however, comes on at varying periods after the incipient symptoms make their appearance. Sexual inclination grows less. The muscular weakness gradually increases, if the disease is not checked, until the patient can barely walk: he totters in his gait, and reminds one of a case of Duchenne's disease. Even before this he sometimes gives up and goes to bed. Often harassing cough ensues, adding its exhausting effect to that of the essential disease. Percussion and auscultation discover consolidation at one apex or over larger areas of the lungs. Dyspepsia and indigestion replace the good appetite which attended the onset of the symptoms, and all efforts to increase the latter are unavailing. The heart begins to flag, and its action is irregular. It finally ceases to act, and the patient dies suddenly, sometimes unexpectedly. Or coma may supervene before death. This coma, known as diabetic coma, is generally ascribed to the accumulation of acetone or acetone-producing substance in the blood. It is supposed to be a product of the decomposition of the sugar in the blood, and the phenomena resulting from its presence are known as those of acetonæmia. Some further account of it will be given in the section on changes in the urine. It is sometimes recognizable by a fruity odor of the breath, which may even pervade the atmosphere of the room in which the patient lies, and may be recognized on entering. It has been compared to the odor of a room in which apples have been kept, again to sour beer, and again to chloroform.

During all this time the thirst and discomfort arising therefrom, continue, although it sometimes happens that toward the end the quantity of urine and its contained sugar diminish and the urine becomes darker in hue.

Such is the course of a typical case of diabetes mellitus. Other symptoms, less conspicuous, are a lowered temperature of the body, from 1° to 2½° F. or even more; cataract, dilatation of the retinal vessels, intraocular lipæmia, functional derangements of vision, including amblyopia, presbyopia, and loss of accommodating power; and occasionally total blindness from atrophy of the retina may be present. I have known almost total blindness to appear very early in the disease, and subsequently to disappear. Derangements of the other special senses, as impairment of hearing, roaring in the ears, and disorders of smell and taste, also occur. Boils and carbuncles are occasional symptoms; although usually late in occurrence, the former are said to be sometimes the first symptoms recognized. Numerous skin affections may occur. Ulcerated surfaces are slow to heal, and gangrene supervenes sometimes spontaneously, but more often as the result of some trifling injury. It may start from a blister produced by cantharides, although such instances are scarcely frequent enough to justify interference with treatment demanding blisters. More frequently surgical operations do badly. Allied to this tendency is a spongy state of the gums, with recession and excavation, resulting, in asthenic cases, in absorption of the alveolar processes and falling out of the teeth. Eczema of the labia and vicinity in females, and a similar irritation about the meatus urinarius in males, are annoying symptoms. A purulent-looking discharge has been seen issuing from the urethra, in which the spores of penicilium glaucum have been recognized by the microscope.

The term diabetic coma is applied to a form of coma which is apt to occur late in the disease, indeed most frequently to terminate it; while it is also used to indicate a train of nervous symptoms of which coma is the terminal one. To this train of symptoms the word acetonæmia is also applied, and should alone be used, while the term diabetic coma should be restricted to the terminal symptom. The coma, as well as the previous nervous symptoms, is considered due to the accumulation in the blood of a product of the decomposition of sugar, formerly believed to be acetone, but now thought to be an acetone-producing substance, probably aceto-acetic acid. It is likely that in all cases of diabetes a small quantity of this substance exists in the blood, from which it is separated by the kidneys and lungs, while it is only when these channels are insufficient for its removal that it accumulates and produces the symptoms described.

Usually, the coma comes on gradually, deepening until it terminates in death. In other instances it is preceded by various symptoms, including dizziness, drowsiness, cephalalgia, delirium, mania, muscular pains, gastric and intestinal symptoms, including epigastric pain, vomiting—sometimes of blood—and even purging; also dyspnoea, with short, panting respiration like that of an animal with both vagi cut, and a fluctuating pulse-rate which continues until coma is established, after which it remains rapid and small. Both the breath and urine may exhale the peculiar odor of acetone, or it may be absent, and the urine strikes the peculiar burgundy-red reaction with perchloride of iron to be again referred to.

These symptoms may be sudden in their occurrence, whence acute acetonæmia, or they may ensue slowly. Ralfe,¹⁷ who has studied the subject of acetonæmia very thoroughly, has called attention to the parallelism between the phenomena of acute acetonæmia and those of acute yellow atrophy of the liver and of phosphorus-poisoning. The sudden, sharp epigastric pain, with gastric disturbance and vomiting, often of blood; the peculiar panting dyspnoea referred to; the short, noisy delirium, followed almost suddenly by deep coma; the fall in temperature as the nervous symptoms develop; the irregular, and finally rapid, pulse,—are all symptoms common to the two conditions.

¹⁷ Clinical Chemistry, 1883, p. 98; also Discussion on Diabetes before Pathological Society of London, Lancet, April 7, 1883, p. 592.

Although acknowledged to be a grave complication, and the most frequent cause of death in diabetes,¹⁸ yet it does not follow that a fatal termination is inevitable when diabetic coma sets in. I have now a patient, a woman, who considers herself in perfect health, but in whom there remains a trifling glycosuria, who at one time was supposed to be dying of diabetic coma.

¹⁸ Of 400 cases of diabetes which passed under the observation of Frerichs, the majority died of acetonæmia (Frerich's "Ueber den plötzlichen Tod und über das Coma bei Diabetes," Zeitschr. für klin. Med., 1883, vi. 3-53). Of 53 persons dying of diabetes at Guy's Hospital, London, during the last ten years, 33 died comatose (Dr. Fred. Taylor, Discussion on Diabetes, Pathological Society of London, Lancet, May 5, 1883). In my own experience acetonæmia has not been so frequent a cause of death as phthisis, acute pneumonia, and heart-failure.

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), Cornillon¹⁹ 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.

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. Fitz²¹ and Louis Starr²² 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.

²⁰ Edinburgh Med. Journal, July, 1872.

²¹ "Diabetic Coma; its relations to Acetonæmia and Fat Embolism," Boston Medical and Surgical Journal, vol. cvi. p. 24, Feb. 10, 1881.

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 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.

²³ Loc. cit.

²⁴ Loc. cit.

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. Heyl²⁶ 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.

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.

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 Laboulbène²⁷ a favorable change.

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 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 Petters²⁸ 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 Jaksch³⁴ 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.

²⁸ Prager Vierteljahrschrift, xiv. 3, 1857, S. 88.

²⁹ Ibid., xvii. 3, 1860, S. 59.

³⁰ Wiener Med. Presse, No. 28, 1865.

³¹ Centralbl. für d. med. Wiss., No. 55, 1874.

³² Liebig's Annalen, Bd. 182, S. 362.

³³ Ibid., Bd. 209, S. 25.

³⁴ Zeitschrift für physiol. Chemie, vi. 6.

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: