Unveiling Diabetes - Historical Milestones in Diabetology. Группа авторов

take out the whole pancreas!”

      “This operation is impossible,” von Mering replied.

Since I did not know about Claude Bernard’s publication stating that no animal would survive total pancreatectomy, and due to my young age, overestimating my capacities as a laboratory surgeon, I exclaimed, “There are no impossible operations. Give me a dog and I will take out his pancreas today.” Von Mehring replied, “Okay, I have a dog and you can try it.” The same day, I performed pancreatectomy in a dog in Naunyn’s laboratory with the assistance of von Mehring. The animal survived and initially seemed to be doing well. The day after the operation, von Mehring had to travel to Colmar because his father-in-law was suffering from severe pneumonia. He had to stay for one week. In the meantime the dog, which had been clean before, started to urinate more and more frequently in the laboratory. I reprimanded the laboratory assistant for not walking the dog frequently enough, but he replied, “I do walk him frequently but this animal is funny. As soon as it returns, it urinates again even immediately after having done it outside.” This observation led me to examine the urine of the dog [6].

Without this controversial discussion on lipids – which had no relation to the final discovery – the experiments would not have been carried out. Von Mering provided the dog and they performed the surgery together in Naunyn’s laboratory that same afternoon. Minkowski was legendary for his manual dexterity, and, as mentioned, had performed the world’s first successful hepatectomy upon a goose (successful in that the creature did not expire immediately). Sauerbruch, a giant in German surgery, called Minkowski “the greatest experimental physiologist of his time.” However, von Mering was also very well trained in experimental physiology – he had worked in the institute of Prof. Ludwig in Leipzig, one of the founders of modern physiology and had published a superlative study on glucose metabolism [7]. In the same institute some years later a young Scottish physician was trained in physiology and published his first paper (in German language), it was J.J.R. Macleod – honored with the Noble Prize for the discovery of insulin.

Fig. 4. The scientific laboratory of Naunyn’s hospital (archives of the Strasbourg University, provided by Prof. Brogard^†, Strasbourg, unpubl.).

      Minkowski and von Mering were a surgical “dream team” and succeeded, in contrast to Claude Bernard, in successfully performing a pancreatectomy. The operation was carried out in Naunyn’s laboratory which was located on Elisabethstrasse near Naunyn’s house.

Thanks to the historic research of Prof. Brogard in Strasbourg we know the floorplan of this laboratory (Fig. 4). Claude Bernard, in his first most productive years, would have dreamt of such a considerable laboratory on two floors with many rooms and personnel. The building does not exist anymore, having been replaced by a catholic chapel, but Elisabethstrasse looks much as it did back in 1889, when the laboratory assistant Josef Zinck would regularly walk the polyuric diabetic dogs.

By chance, von Mering was not present when Zinck reported to Minkowski that the dogs were urinating frequently. Both collaborated to write the papers. Minkowski had to perform pancreatectomy in more dogs, the first one had been treated with phlorizin beforehand by von Mering and Minkowski wanted to be sure that glucosuria was not simply a consequence of the administration of phlorizin. The results were published in June 1889 and with more details in 1890 [8, 9] (Fig. 5). It was a masterpiece of a succinct publication – the title provides the full message: Diabetes Mellitus following the Extirpation of the Pancreas. In September 1889 Minkowski and von Mering attended the first World Congress of Physiology in Basel accompanied by a pancreatectomized dog. It was the highlight of the conference and von Mering and Minkowski became famous worldwide.

Fig. 5. The famous publication on pancreatic diabetes, 1889 [8].

In April 1894, Elliott Proctor Joslin, already a renowned specialist in diabetes research, praised the discoveries of Minkowski and von Mering in the Boston Medical and Surgical Journal (in 1928 the name changed to New England Journal of Medicine). Joslin summarized: “The experimental work of Herr [sic!] von Mering and Herr Minkowski on the production of diabetes by pancreatic extirpation, forms one of the foremost chapters in all experimental pathology… The abdominal grafts of the pancreas are by far the most striking part of Minkowski’s and von Mering’s work. The art of the experimenter is here given full range. The pancreas is a fragile organ and quickly dies. Moreover, an animal which has been submitted to an operation on the gland is in great danger of peritonitis. Both obstacles were overcome in the following manner. The pancreas was carefully dissected from its attachments in the abdominal cavity, turned on its axis and stitched to the abdominal wall. The blood supply was disturbed as little as possible. The wound was allowed to heal, and gradually the pancreas became engrafted on its new surroundings. When this was firmly established the dog was submitted to another operation, in which the internal part of the gland was removed. On the recovery of the animal no diabetes resulted. After an interval of some time, the engrafted pancreas was removed; and when this was done, diabetes in all its forms appeared. What more striking proof could be asked for the action of the pancreas in producing diabetes?” [10]

However, there is one mistake in the Joslin’s report: von Mering was not present when the grafting experiments were carried out. After the first discovery the following research on pancreatic diabetes was performed exclusively by Minkowski. Three reasons which may explain why von Mering did not continue diabetes research are, firstly, that following some unsuccessful applications Josef von Mering was nominated in 1890 in the University of Halle an der Saale and therefore moved with his wife and his four children from Strasbourg to Halle in April 1891. The second reason is that in Halle he had signed up for an incredibly multitasking life – becoming director of the Medical Polyclinic (which included medical teaching), lecturing on otorhinolaryngology, medical chemistry, and legal medicine, as well as becoming head of department in a Catholic hospital in Halle. The third reason is that von Mering worked, with great success, in many different areas of research. He, together with the Noble prize winner Emil Fischer, discovered the first barbiturate. Indeed, von Mering also holds the accolade of having published the first clinical paper on paracetamol. Freiherr Josef von Mering, born in 1849 in Cologne, died in 1908 in Halle an der Saale. Despite his numerous discoveries there is neither a renowned academic prize, a street, nor a plaque on the places where he lived to commemorate this outstanding researcher. This may change in the future since his discovery of “phlorizin diabetes” was the beginning of the use of SGLT inhibition in diabetes care over 100 years later [11]. In contrast to von Mering, Minkowski continued diabetes research throughout his career. In the first years after the discovery of pancreatic diabetes he had to reply to numerous voices of criticism, particularly that of Eduard Pflüger [12].

Minkowski married Marie Johanna Siegel in 1894. Their two children, Rudolph and Laure, were born in Strasbourg (Fig. 6). As usual in the realm of an academic career, he had to look for a position as head of department. His applications to universities were unsuccessful, and some authors assume that German faculties were reluctant to call for