It is said that the sweet taste of diabetic urine was familiar to Susruta, a physician who lived in India during the seventh century. The disease, then as now, may have been more prevalent among the Hindoos than elsewhere in the world. In Europe the sweet taste of diabetic.urine was discovered by Thomas Willis in 1674, but it was not till after another hundred years that Dobson, in 1715, showed that the taste was due to the presence of sugar. Subsequently the coexistence of a hyperglycemia was established.

Claude Bernard found that the stimulation by puncture of a group of cells (the "diabetic center") lying in the medulla near the floor of the fourth ventricle gave rise to an excretion of sugar in the urine. This experiment is the source of the false impression that diabetes is essentially of nervous origin. It is called la piqure.

Diabetes1 is a disease of particular interest, since it is a departure from the physiologic condition involving the capacity of the organism to care for sugar in the normal fashion. All the symptoms are due to this one fact. No other disease has been more thoroughly investigated. The study of diabetes has wonderfully developed a knowledge of the intermediary metabolism of protein, fat, and carbohydrates. In presenting the details to the reader it may be remarked that the work done is prophetic of possible accomplishment along scientific lines in the study of disease. It is typical of that "scientific medicine" which affrights the spirits devoted to a passing empiricism.

1 For an excellent monograph on this subject consult Foster, "Diabetes Mellitus," 1915.

The foundation of modern knowledge on this subject was laid by von Mering and Minkowski1 and by Minkowski2 working alone, who extirpated the pancreas in dogs and demonstrated that such animals became diabetic.

Peligot3 long ago showed that the sugar in diabetic urine was glucose. Geelmuyden4 analyzed more than 30 diabetic urines which contained much sugar and could not detect the presence of maltose or any of the known disaccharids, though he suspected the presence of monosaccharids other than glucose. Von Noorden5 states that fructose appears in the urine in cases of severe diabetes.

The causes of the appearance of sugar in the urine are: (1) Either the organism cannot burn sugar, which therefore accumulates in the blood in excess of the normal, and is filtered through the kidney (diabetes mellitus, experimental pancreas diabetes); or (2) some tissues may lose their sugar-retaining function so that the normal regulatory control of the quantity of blood-sugar is lost or diminished (Bernard's piqure, alimentary glycosuria, phlorhizin glycosuria).

The stimulation of Bernard's "diabetic center" is effective in its results only when the liver contains glycogen.6 This form of glycosuria cannot be obtained in a starving animal. It is attributed to a sudden flushing of the liver with blood and a conversion of glycogen into sugar, so that hyperglycemia and sugar elimination through the kidney follow.

Ishimori,7 working under Hofmeister's direction, concluded that although in the fasting rabbit glycogen disappeared in the liver from the periphery of the lobule toward the center without evidence of glycogen as such appearing to be discharged, in the case of piqure, glycogen itself passed from all the cells into the surrounding lymph-spaces and dilated bloodvessels. It has been suggested that piqure acts through a stimulation of the adrenal secretion, but Freund and Marchand1 find after the extirpation of the adrenals that piqure causes hyperglycemia, and argue that the adrenals are not the cause.

1 von Mering and Minkowski: "Archiv fur exp. Path, und Pharm.," 1890, xxvi, 371.

2 Minkowski: Ibid., 1893, xxxi, 85.

3 Pe1igot: "Compt. rend, de l'Acad. des Sciences," 1838, vii, 106. 4 Geelmuyden: "Zeitschrift fur klinische Medizin," 1910, lxx, 287. 5 von Noorden: "Diabetes," 1905, p. 50.

6 Dock: "Pfluger's Archiv," 1872, v, 571.

7 Ishimori: "Biochemische Zeitschrift," 1912-13, xlviii, 332.

Hofmeister2 has discovered that the fasting organism is more susceptible to alimentary glycosuria than the well-fed one. He calls such a condition "starvation diabetes" (see below).

Asphyxial glycosuria, discovered by Araki, has already been described (see p. 422). Macleod3 found that if the liver were excluded from the circulation by means of an Eck fistula in the dog no hyperglycemia followed asphyxiation. Furthermore, severance of the hepatic nerves did not prevent asphyxial hyperglycemia. Macleod therefore concluded that acids carried in asphyxial blood produced glycogenolysis in the liver cells. Analogous results were obtained by Blum,4 who found that strychnin convulsions freed a dog's liver of its glycogen even after cutting the vagus and splanchnic nerves. He concluded that chemical co-ordination was established through the blood between the muscle cells in need of sugar and the liver which could supply it.

Elias5 found that the intravenous injection of acids into dogs resulted in a discharge of glycogen by the liver in hyperglycemia and in glycosuria. He suggested that the acidosis in diabetes mellitus might exert a similar influence. In a later paper Elias and Kolb6 state that the hunger diabetes of Hofmeister is due to the reduced alkalinity of the blood which accompanies fasting. Administration of alkali reduced or prevented this form of glycosuria. Hence, acidosis prevents the normal storage of glycogen.

1 Freund and Marchand: "Archiv fur exp. Path, und Pharm.," 1914, lxxvi, 324.

2 Hofmeister: Ibid., 1890, xxvi, 355.

3 Macleod: "American Journal of Physiology," 1908-09, xxiii, 278.

4 Blum, P.: "Pfluger's Archiv," 1915, clxi, 516. 5 Elias: "Biochemische Zeitschrift," 1912-13, xlviii, 120. 6 Elias and Kolb: Ibid., 1913, lii, 331.

The acidosis which rapidly develops in both pancreas and phlorhizin glycosuria is, therefore, the cause of the almost complete removal of glycogen from the liver.