developed by the Germans Carl August Trommer in 1841 and, with better luck, in 1848 by Hermann Christian von Fehling (1811–1885) [22], who developed the method used to measure glycosuria almost to the present day. These developments were not universally acknowledged, anyway, and leveraging upon rare cases of renal diabetes and other non-diabetic “melliturias,” detractors fought fierce diatribes which endured well into the first half of the 20th century.
Sweet Blood
Already in 1806, the Englishman Willian Hyde Wollaston (1766–1828) had shown the presence of sugar in the blood in a proportion of 1:30 to the amount found in urine and, in 1843, Thomas Watson also developed a method to measure glucose in the blood, the clinical use of which was seriously hampered by the requirement of at least 300 mL for a single assay. The first to show that the liver can release glucose into the blood and, more generally, to propose a model of the human body as a set of collaborating parts maintaining an internal balance (“milieu interieur”) was the Frenchman Claude Bernard (1813–1878), father of experimental medicine. This replaced the then dominant concept of various organs as separate entities not communicating with each other except through the ill-defined “humors.” Bernard theorized in 1855 that diabetes was the result of an overproduction of glucose by the liver, a revolutionary vision for its time and still valid today [23]. He found that ligation of the pancreatic ducts results in degeneration of the gland, an observation that was to carry important consequences. To him we also owe the first reliable method of measuring the concentration of glucose in the blood.
The Pancreas and Diabetes
In 1685, at the dawn of experimental medicine, the Swiss Johann Conrad Brunner (1653–1727), who described the homonymous glands in the duodenum, removed the pancreas from a dog in the course of his studies on the role of pancreatic juices in digestion [24]. To contrast the theories of Frans de la Boë (Sylvius of the mesencephalic aqueduct) and his pupil Reigner de Graaf, who described the exocrine pancreas, on October 6, Brunner removed the “pars caudalis” (the head) and ligated the ducts of the “pars superior” (the body and tail) of the dog’s pancreas (Fig. 10). He then described with great precision how, after the operation, the poor animal began to urinate abundantly, drink a lot, and waste away despite the large amount of food ingested. Unfortunately, focusing on his line of research, Brunner failed to relate the symptoms, which he attributed to generic postoperative disorders, to what was already widely known about diabetes. Upon dissection 7 months later, on May 12, 1686, he found the remaining pars superior atrophic (“indurata et grandinosa”).
Fig. 10. Frontispiece and illustration of pancreatectomy in Joseph Conrad Brunner’s Experimenta nova circa Pancreas atque Diatribe de Lympha and genuine Pancreatis Usu. London, 1722. The Museum of Diabetes, Turin. www.museodeldiabete.it. Reprinted with kind permission.
Of interest, in 1788, is a report by Thomas Cawley, chief surgeon of the British Army in Jamaica, of a hardened pancreatic gland, embedded with calculi, at the postmortem of a person affected by diabetes. At any rate, he continued to ascribe diabetes to the “morbid dilatation of the uriniferous tubes” [25].
However, not all patients with diabetes had the same characteristics and, importantly, the same prognosis. Apollinaire Bouchardat (1806–1886), professor of hygiene and chief pharmacist at the Hôtel-Dieu in Paris, compiler of the official Formulaire for the French Ministry of Health, started to distinguish a “diabète maigre” in individuals young, lean, with severe symptoms and a poor outcome, from a “diabète gras” in those overweight in whom a milder form of disease presented later in life and who could survive longer on a low-calorie diet. Bouchardat suggested as first measure the suppression of bread and almost all other carbohydrates but conceded their partial reintroduction after the disappearance of glycosuria, which the patients could detect alone by tasting their own urine, a first in patient self-management. Bouchardat’s regime also included abundant amounts of protein and fat, a good bottle of red wine a day, days of complete fasting, avoidance of anger, and vigorous exercise in the open air [26, 27].
Arnaldo Cantani (1837–1893), director of Medicine at Naples University and the first Italian diabetologist, prescribed true starvation diets, albeit “fat and rich in meat,” and it seems he used to lock the poor glycosuric patients in, so that they would not transgress [28]. In 1869 the 22-year-old German medical student Paul Langerhans (1847–1888) described in his doctoral thesis the presence of small agglomerations or “islands” of cells in the pancreas, with characteristics which differed from those of the rest of the organ [29]. Of course, he was unaware that what would come to be known as “islands of Langerhans” produced insulin and, indeed, never knew that he had opened a seminal chapter in medicine and never dealt with diabetes in the remainder of his short life [see the chapter by Jörgens; this vol., pp. 25–35].
Twenty years later, in 1889, the story of Brunner repeated itself in the University clinic of Strasbourg directed by Bernhard Naunyn (1839–1925), himself interested in the problems of metabolism. In 1889, Joseph von Mering (1849–1908) and Oskar Minkowski (1858–1931) were studying the role of the pancreas in digestion and removed the organ from a dog. Again, all the symptoms of diabetes appeared after the operation. This time, however, Minkowski, who had carried out the surgery, rushed to analyze the dog’s urine and found glucose in large quantities. He then repeated the operation in other animals with the same result and concluded that the pancreas produces some substance capable of decomposing the sugar in the blood, in the absence of which diabetes appears [see the chapter by Jörgens; this vol., pp. 40–50] [30].
After Minkowski’s discovery, researchers attempted to extract from the pancreas the mysterious agent that could cure diabetes. Minkowski himself, in 1890, grafted fresh pancreatic fragments under the skin of another diabetic dog, temporarily reducing glycosuria. In 1893, the French Gustave-Édouard Laguesse (1861–1927) suggested that the islands of pancreatic tissue described by Langerhans might be the source of the substance involved in blood glucose control [31]. Among others, in 1893, Ferdinando Battistini (1867–1920) in Turin injected an aqueous-glyceric extract of bovine pancreas into 2 young patients for a few days, albeit without modifying the course of their diabetes [32]. Like the grafts, pancreatic extracts, obtained with various methods, proved ineffective, toxic, or both.
During the following 30 years more evidence accumulated that the elusive antidiabetic factor came from the islands. The name “insulin,” from the Latin “insulae,” was proposed in 1909 by the Belgian Jean de Mayer (1878–1934) and in 1910 by the Englishman Sir Edward Albert Sharpey-Schafer. In 1909, the Berliner Georg Ludwig Zülzer (1870–1949) [see the chapter by Jörgens; this vol., pp. 58–72] came close to the solution by producing an alcoholic extract of bovine pancreas (Acomatol) but this proved toxic at first and then induced seizures in dogs, possibly due to severe hypoglycemia [33]. In 1916, Nicolas Constantin Paulescu (1869–1931), professor of physiology in Bucharest, injected
