Читать книгу Unveiling Diabetes - Historical Milestones in Diabetology - Группа авторов - Страница 59

Georg Ludwig Zülzer (Fig. 1) was the closest of all the “precursors” to the discovery of insulin and its successful application for the treatment of diabetes. His father, Prof. Wilhelm Zülzer (1834–1893), came from a wealthy Jewish family in Breslau (now Wroclaw), which probably had their roots in the Jewish city of Zülz in Silesia. He worked at the Charité in Berlin and became known for his publications in epidemiology and urology. His son, Georg Ludwig Zülzer, was born on April 10, 1870 in Berlin. After medical studies in Freiburg and Berlin he worked as an assistant in various clinics, among others with the metabolism researcher Prof. Raphael Lépine in Lyon. In Giessen he met his later friend, the endocrinologist Ferdinand Blum. In 1901, Blum described “adrenalin diabetes.” This inspired Zülzer to come up with an idea regarding the pathogenesis of diabetes, which he formulated in 1907. He suspected that diabetes was caused by an imbalance between the secretion of adrenaline and the blood sugar-lowering substance from the pancreatic islets [1]. Blum later founded a research institute for endocrinology in Frankfurt but was forced to immigrate to Switzerland in 1939.

Fig. 1. Georg Ludwig Zülzer. From Mellinghoff [1].

Zülzer opened a private practice in Berlin in 1900. Occasionally it is stated in the literature that he worked as a pediatrician. This however is a case of mistaken identity as it was his son who became a renowned researcher in pediatrics in the USA. Zülzer dealt with internal medicine, and he also wrote a two-volume textbook on this subject [2]. In 1908 he became chief physician at the Hasenheide Clinic in Berlin (Fig. 2). After the First World War he became the head of the Department for Internal Medicine in the Hospital Berlin Lankwitz [1].

Fig. 2. The hospital Hasenheide in Berlin, where Zülzer’s laboratory was located (postcard, collection Dr. V. Jörgens).

For 12 years – from 1902 to 1914 – Zülzer conducted research aiming at the production of a pancreatic extract for the treatment of diabetes. In the first years he used the laboratory of the institute of Prof. T.W. Engelmann in Berlin. Eight publications and three patent specifications bear witness to this tireless work. He first injected adrenal extract into rabbits and glucosuria occurred. When he injected his pancreatic extract at the same time, this increase of glucosuria did not occur. He did not describe all the details of the methods he used to produce the extract in these early studies [3]. However, he wrote: “In order to obtain a pancreatic preparation that is not too toxic, all proteins of the pancreas must be removed” [3]. At first, Zülzer tried to obtain pancreata from the slaughterhouse, but this proved to be very difficult. Then he came up with the idea of sacrificing large dogs and using theirs. In the hope that the pancreas would then contain more of the hormone, he fed the animals plenty of carbohydrates beforehand. He stated later in his US patent application: “The pancreas preparation may be made as follows: the pancreas gland of an animal in narcosis is laid bare, the animal being preferably in a state when the process of digestion is at its height, the principle efferent vein is ligatured... In a similar manner the remaining veins of the pancreas are tied and swell greatly after the first ligature. After one or two hours the pancreas is removed for further treatment. This treatment consists in cutting it up into small pieces, leaving the same to self-digestion under weak alkaline reaction for several days, although this self-digestion may be omitted. Then precipitating the albuminous bodies by means of alcohol or by boiling” [4].

Zülzer also tried to treat some patients with his extract (in other hospitals, since at his own he did not find suitable cases of diabetes). He presented the results on June 15, 1908 during a meeting on internal medicine in Berlin. He summarized the results as follows: “Intravenously administered this hormone of the pancreas was able to decrease glycosuria and acetonuria for some time” [5]. He did not supervise the patients correctly since they were in different hospitals and the data were not totally convincing. Nevertheless, the results of his research are already quoted in the first textbook on endocrinology, published in 1910 by the Viennese Prof. Arthur Biedl, one of the founding fathers of endocrinology [6].

In later years, Zülzer modified the production of his preparation without describing it more precisely. In contrast to Banting and Best, Zülzer assumed that the hormone was not a protein; he hoped that a prolonged incubation of the crushed pancreas would lead to a breakdown of proteins and therefore result in a better extract – an error! It is interesting that he sometimes did not practice this incubation. This may explain why only some of his extracts were effective and others not. Like Banting and Best, Zülzer used alcohol for extraction. However, in Toronto the chemist Collip achieved a much better degree of purity than Zülzer by doing the following: “He used acid alcohol as the initial extractive but raised the alcohol concentration to about 80%. By this means certain inert objectionable materials were removed. The inert materials were filtered and the insulin precipitated from the alcohol solution by raising the concentration of alcohol to approximately 92%” [7]. Zülzer certainly produced effective extracts, but also repeatedly ineffective samples. This explains the very different results of the experiments on animals and also on people with diabetes. The funding of the work was also difficult. The Schering Co., which had initially financed the investigations, then revoked this financial support. In 1908, Zülzer tried in vain to obtain a scholarship from the University of Berlin for the Zoological Research Institute in Naples. Many years before, Paul Langerhans had received such a scholarship, but Zülzer did not have a godfather named Rudolf Virchow. Zülzer had applied for the extraction of insulin from the insular organ of fish in Naples. If he had been granted these 500 marks, it may, in all probability, have helped him to develop a very effective insulin preparation.