Unveiling Diabetes - Historical Milestones in Diabetology. Группа авторов
new method to remove the pituitary gland in animals by an intracranial subtemporal route. Harvey Cushing described Paulescu’s results as “by far the most important contribution to the subject” and Cushing used Paulescu’s method in neurosurgery which made him famous [20]. Motivated by Prof. Albert Dastre, Paulescu commenced work with the objective of isolating and studying the “active substance of the internal secretion of the pancreas,” but there are no publications about these experiments [24]. Dastre held the Chair of General Physiology at the Sorbonne, following Claude Bernard and Paul Bert.
In 1900, Paulescu returned to Romania where he had been appointed assistant professor of physiology. In 1904 he became Head of the Physiology Department of the Bucharest University Medical School. However, he needed the contact to clinical medicine and therefore served, in addition, as consulting physician at the St. Vincent de Paul Hospital.
In Bucharest Paulescu continued his research on the pituitary gland. However, inspired by the publications of Zülzer in 1908, he chose to return to diabetes research. In 1916, he observed that an extract he had produced from pancreas tissue improved metabolic control in pancreatectomized dogs. Alas, bad luck and political upheaval would intervene. In 1916 a new King was crowned in Romania and the country entered into the First World War. Despite the fact that the King originated from the Hohenzollern family, like the German Emperor, he joined the Entente and invaded the Austro-Hungarian Empire on August 27, 1916. It turned into a total disaster, Austria, substantially supported by the German army, petrified the Romanian army and on December 16, 1916 the city of Bucharest was conquered. There was no way for Paulescu to continue any research until the armistice of 1918. The land area of Romania subsequently doubled, but the vast majority of the new inhabitants were not Romanians. In particular, the annexed Moldova and Bessarabia had an important Jewish population. Romanian politics then entered a dark period of racism and antisemitism.
Insulin Discovered in Bucharest
Once the war was over Paulescu resumed his research. Following the publication of preliminary data on July 23, 1921 [25, 26], he summarized his results in a publication submitted on June 21 and that appeared in the Archives Internationales de Physiologie on August 31, 1921 [27]. At the time this journal would have been considered a top-level international journal. He demonstrated a decrease of hyperglycemia following an intravenous injection of his extract in pancreatectomized dogs, whereby a temporary suppression of glucosuria and a remarkable decrease in acetonemia and ketonuria occurred. Likewise, he showed that the effect on blood glucose starts within the hour immediately following the injection and lasts approximately 2 h. It was technically difficult for him to measure glycemia very frequently, he used Pflüger’s method, requiring 25 mL of blood, whereas in Toronto they needed far less blood. Paulescu named his extract “pancréine” and, on April 10, 1922, the Minister of Industry and Trade in Romania gave him the patent number 6254 with the title: “The pancréine and the manufacture process.” He injected his extract into 2 patients with diabetes, but side effects showed that the extracts needed further purification. He tried to obtain funding for the production but the lack of any pharmaceutical industry in his country, and certainly the subsequent news from Toronto, meant that he did not get any support [28].
Fig. 8. The work of Paulescu quoted by Macleod [30].
Banting and Best published their results in the Journal of Laboratory and Clinical Medicine in 1922. They only quoted Paulescu’s earlier publication [25] and not the full paper in the more relevant journal [26]. In their introduction, they wrote: “Paulesco has recently demonstrated the reducing effect of whole gland extract upon the amounts of sugar, urea and acetone bodies in the blood and urine or diabetic animals. He states that injections into peripheral veins produce no effect and his experiences show that second injections do not produce such marked effects as the first” [28]. Later in the paper, summarizing the literature they state: “We may conclude, that all injections of whole gland extract have been futile as a therapeutic measure in defects of carbohydrate utilization” [28]. The reviewers of the journal overlooked this bizarre and contradictory formulation. It can be interpreted as if Paulescu’s work was irrelevant. Why the authors chose this formulation is unclear. In his monograph “Carbohydrate Metabolism and Insulin” (authored alone without Banting), J.J.R. Macleod mentions Paulescu’s work in detail [29]. He reports that in Toronto they were aware of the publications by Paulescu – more precisely they “got to know them during their ongoing research” [29], and in his book presented a convincing Table from Paulescu’s publication (Fig. 8).
In 1923 the Noble Prize was awarded to Banting and Macleod. Letters were immediately sent by Paulescu and Zülzer to Stockholm claiming their precedence in the discovery of insulin. However, they had not been nominated, as well as Minkowski, who had been nominated several times but not for the prize in the year 1923. A nomination is a formal prerequisite for the Nobel Prize Committee to consider applications. In the following decades, it was Prof. Pavel from Bucharest who particularly fought for the commemoration of Paulescu. Upon his request, a committee was set up by the International Diabetes Federation (IDF) to publish a statement on the issue, Pavel was quite upset that nobody from Bucharest was part of this committee [20]. He wrote to Charles Best asking him to clarify the reason why Paulescu’s work was misquoted by Banting and Best. Charles Best replied in a letter to Prof. Pavel on September 15, 1969: “I cannot recollect, after this length of time, whether we relied on our own poor French or whether we had a translation made. In any case I would like to state how sorry I am for this unfortunate error and I trust that your efforts to honor Prof. Paulescu will be rewarded with great success” [20].
Michael Bliss, the undisputed elite expert concerning the discovery of insulin, summarized the issue in 2003 as follows [30]:
In fact, Banting and Best had not produced results more impressive than Paulesco’s. Indeed, as Banting had had the honesty to write of the first clinical test of their extract, the results had not been as impressive as those produced by another predecessor, Zülzer, in 1908. The final irony of the Banting and Best myth was that it could not meet its own incomplete criteria; Banting’s and Best’s research was so badly done that, without the help of Macleod and Collip, and a much more subtle view of the constituents of the discovery of insulin, the two young Canadians would be fated to disappear from medical history… Throughout his later life Charles Best worked very hard and with considerable temporary success, to convince every one of his and Banting’s claims to be the sole discoverers of insulin. In the long run he failed.
Rise and Fall of Glory
Paulescu was posthumously elected a member of the Romanian Academy in 2001. A bronze statue in honor of Paulescu was inaugurated in Bucharest on the occasion of the 80th anniversary of the publication of Paulescu’s paper on his discovery