United Nations Diabetes Day | A Century of Insulin in China

Insulin was discovered in 1921 and is considered one of the earliest drugs in medical history that can demonstrate the miraculous power of modern medicine[1]. In 1922, the drug was successfully used in clinical practice and commercialized, and its discoverer won the Nobel Prize in Physiology or Medicine the following year[2]. In 1923, insulin was introduced to China and used in clinical practice, and it has been exactly 100 years since then[3]. In the past 100 years, insulin has played an irreplaceable role in the field of diabetes treatment and has changed the lives of many patients.

Before insulin was introduced to China, scholars such as Franklin C. McLean, the first director of the Department of Internal Medicine at Peking Union Medical College Hospital, actively introduced the characteristics of insulin and the latest information on clinical trials to the academic community, and tried to produce insulin in China, but no materials have been found to detail this period of history [3-4]. On the occasion of the 100th anniversary of the introduction of insulin to China, the author used historical materials such as archives, medical journals of the Republic of China, and the annual reports of Peking Union Medical College Hospital to write a short article to trace this little-known history, hoping to enrich the history of pharmacy, diabetes, and the history of Peking Union Medical College and the hospital.

Author: Gu Xiaoyang

Capital Medical University School of Medical Humanities

Introduction and production of insulin by the Department of Internal Medicine of Peking Union Medical College Hospital

1 MacLean's first introduction to insulin

In May 1922, the University of Toronto insulin research team reported all the experimental research results since 1921 at the American Medical Association Symposium and officially announced that insulin had been extracted from animal pancreas. This meant that diabetes, which had long been regarded as an "incurable disease", had a new treatment drug. This news immediately received a warm response and widespread attention from the academic community [5].

However, the Toronto team and the Canadian doctors who participated in the early experiments were still unsure about the dosage and drug response of insulin for patients. Therefore, they decided to conduct clinical research in collaboration with some medical experts in North America. All researchers conducted independent observations in their respective medical institutions, but would learn about the research results of others and exchange opinions through correspondence, conferences, and other forms of discussion [6].

The first experts to conduct clinical trials on insulin included Russell M. Wilder , a famous endocrinologist from the Mayo Clinic. In November 1922, Wilder went to Ontario, Canada to attend a diabetes clinical expert meeting organized by John Macleod, the discoverer of insulin and professor at the University of Toronto, and held discussions with other researchers[7].

At the end of January of the following year, his team completed the article “ Clinical Observations on Insulin ”. In May 1923, Wilder and other experts who were the first to use insulin published the results in the Journal of Metabolic Research (J Metab Res) (Figure 1), which was the world’s first summary of expert opinions on the clinical application of insulin [8].

Figure 1. The paper published by Wild et al. in J Metab Res[8]

While summarizing the research, Wilder conveyed his and other experts' experience in using insulin to his old friend, McLean , the first director of the Department of Internal Medicine at Peking Union Medical College Hospital (who had just stepped down as president of Peking Union Medical College at the time).

On February 15, 1923, MacLean compiled the literature he had read and the expert opinions he had mastered, and gave a report titled “ The present status of insulin therapy in diabetes ” at the academic conference of the China Medical Missionary Association. This was the first known report to systematically introduce insulin to the Chinese medical community, and it introduced insulin therapy for diabetes from seven aspects [9]:

(1) Historical review of the discovery of insulin;

(2) The chemical properties of insulin;

(3) The physiological effects of insulin;

(4) The role of insulin in the treatment of diabetes;

(5) Clinical considerations for insulin (this part of the information comes from Wilder);

(6) Indications for the use of insulin;

(7) Summary.

It can be said that this report brought the first detailed interpretation of insulin to scholars in China.

Figure 2 McLean’s lecture notes published in the journal of the Chinese Medical Association[9]

2 Proposal for the production and distribution of insulin by the Department of Internal Medicine of Peking Union Medical College Hospital

After understanding the characteristics of insulin, Chinese doctors still face a serious problem: there is no medicine available . McLean obviously paid attention to this situation and mentioned in the last part of the report the motion of producing and distributing insulin by the Department of Internal Medicine of Peking Union Medical College Hospital.

As early as December 1921, when the University of Toronto research team reported preliminary research results at the American Physiological Society Annual Meeting, George Clowes, a research director and biochemist at Eli Lilly & Co., who was present at the meeting, was keenly aware of the huge commercial value of insulin as a new drug. He immediately contacted MacLeod after the meeting and expressed that Eli Lilly was willing to cooperate with the University of Toronto to promote the commercial production of insulin. However, MacLeod's team did not want to gain commercial benefits from insulin, so they rejected Eli Lilly's request for cooperation.

In 1922, as clinical trials of insulin progressed, the demand for insulin far exceeded the stable production capacity of the University of Toronto and its collaborating Connaught Laboratories. Scientists at the University of Toronto decided to accept Eli Lilly's invitation to cooperate and take active measures to standardize the commercial production of insulin.

In order to manage issues such as the dissemination of insulin production technology, commercial production licenses, and patent authorization, the University of Toronto established a special Insulin Committee[2]. Considering the huge commercial profits brought by insulin production, most medical scientists involved in early clinical trials agreed that the University of Toronto Insulin Committee should manage patents to prevent criminals from making money and harming lives by selling counterfeit insulin[7].

At the same time, McLean and others were also closely following the development of insulin research. In October 1922, the Peking Union Medical College wrote to McLeod to contact him about transporting insulin to China. McLeod forwarded the letter to Cruise, entrusting Eli Lilly to coordinate the matter, and said:

“I think some insulin should be shipped to China. After all, we have already established pharmacologically and clinically that the drug is effective. The report from Beijing will give us further information on how effective the insulin is after it has been shipped.” [10]

It can be seen that at this time, McLeod was not sure whether the insulin could still maintain its effectiveness after a long sea voyage.

According to MacLean, Eli Lilly initially rejected the Union Medical College's request:

“Given that insulin is currently only available in solution form with uncertain stability, manufacturers do not plan to ship it to China.”

With ocean transportation hopeless, McLean further expressed Peking Union Medical College Hospital’s intention to produce insulin:

"We therefore hope to prepare our own insulin, initially for use in our hospitals... Ultimately, unless a stable source of commercially prepared insulin is available in the meantime, we hope to prepare for distribution in China under distribution regulations adopted in the United States, subject to the approval of the patent owner." [9]

On December 11, 1922, the University of Toronto Insulin Committee decided to “authorize MacLean of the Peking Union Medical College Hospital to be responsible for the manufacture and distribution of insulin in China”[11]. This event was also recorded in the Peking Union Medical College Hospital’s 1923 annual report:

"Dr. McLean was appointed by the Toronto Insulin Committee to oversee the distribution of insulin in China. According to the committee's rules, insulin can only be distributed to those who have sufficient knowledge of this new diabetes treatment. The Department of Internal Medicine is prepared to provide training for all unqualified and inexperienced physicians who apply to use insulin." [11]

While Peking Union Medical College Hospital was planning to produce insulin, another incident occurred in the United States, which ultimately changed the decision of the insulin committee and affected the process of insulin production. From late 1922 to early 1923, Eli Lilly completed an important technological innovation, which greatly improved the stability and production of insulin by adjusting the pH of the insulin solution.

In March 1923, Cruise stated:

“Eli Lilly produces enough insulin for the entire world” [2].

It is likely that it was because of this technological innovation that Eli Lilly changed its previous decision and decided to export insulin to China.

In May 1923, the Insulin Committee made it clear that it would not grant China an insulin patent.[12] Clearly, the original insulin production plan failed to materialize. In July, Peking Union Medical College Hospital began to use insulin shipped by sea in clinical practice. On the first page of the medical record, the intern who wrote the medical record, Hou Xiangchuan, who later became a famous nutritionist, solemnly recorded: " This is the first diabetic patient in our hospital treated with insulin! "[3]

The discharge record of the first patient using insulin in Peking Union Medical College Hospital

The first patient using insulin in Peking Union Medical College Hospital had a medical record on the second day of admission

The clinical application of insulin in Peking Union Medical College Hospital was not only driven by Eli Lilly's decision to export the drug to China. As early as when he first introduced insulin, McLean warned that the chemical properties of insulin were not well understood, and the production method was not standardized and was still in the experimental stage.

When using insulin clinically, doctors need to deal with many difficulties. For example, injected insulin cannot have the same precise regulation mechanism as self-produced insulin, so doctors need to strike a delicate balance between carbohydrate intake and insulin dosage; insulin needs to be administered multiple times, and doctors need to always pay attention to whether the patient has hypoglycemia, etc. The ideal method is to monitor blood sugar frequently, but this is simply impossible for patients who are treated at home.

The only feasible method at that time was

“Insulin is used in hospitals, and the hospital must have adequate experimental facilities and a well-functioning dietary department as a back-up; after a period of time, when the dietary intake and insulin dosage are basically determined and the patient has learned to manage his or her own diet, he or she can take the medicine home and have long-term follow-up visits.” [9]

In 1923, Peking Union Medical College Hospital not only had insulin shipped by sea, but also had the above-mentioned conditions: in terms of diet, the hospital established the Nutrition Department (originally named the Dietary Department) as early as 1921, laying the foundation for the configuration of diabetes diets.

In 1923, the hospital arranged two diabetes clinic doctors to specialize in researching and preparing food for patients[13]. As the nutrition department became more and more complete, the "special kitchen" in it later prepared meals for diabetic patients[14-15].

In terms of blood sugar testing, in the early 20th century, biochemistry gradually separated from physiology and became an independent field, and blood biochemical testing also made great progress. One of the most outstanding achievements in the field of clinical blood biochemistry is the classic blood sugar testing method, the Folin-Wu method, jointly invented by Wu Xian of the Department of Biochemistry of Peking Union Medical College and his mentor during his studies in the United States, American biochemist Otto Folin .

[Click to view link] The ten-year debate on blood sugar measurement method - the secret history behind the "Folin-Wu Xian" method

In 1920, after Wu Xian returned to China to work, he personally promoted and applied this simple and rapid method of measuring blood sugar[16]. The establishment of the clinical blood biochemistry laboratory department and the nutrition department was an indispensable condition for the clinical application of insulin in Peking Union Medical College Hospital.

3. Additional remarks

In early 1923, MacLean estimated that it would be very expensive to produce insulin in China[9] and that producing insulin was only a temporary option when insulin could not be imported. Once good-quality commercial insulin preparations were delivered steadily and could meet clinical needs, the urgency of producing insulin would no longer exist.

After the source of insulin was resolved, doctors at the Department of Internal Medicine of Peking Union Medical College Hospital began to summarize the use of insulin in clinical practice. The clinical characteristics of diabetes in Chinese people and the pharmaceutical properties of insulin were also increasingly clearly outlined [17-18].

In 1937, Wang Shuxian, an internal medicine doctor at Peking Union Medical College Hospital, published the earliest clinical study on diabetes in China and the only one with a large number of cases before 1949 , Diabetes: Analysis of 347 Chinese Hospitalized Patients , which was the culmination of diabetes research in China at that time [19-20]. The many experiences in diabetes diagnosis and treatment accumulated by Peking Union Medical College Hospital became an important basis for the discussion of the first "Diabetes Symposium" after the founding of the People's Republic of China [21]. The accumulation of these clinical experiences was based on the introduction and production initiative of insulin in 1923.

From the introduction of insulin by Peking Union Medical College Hospital and the short history of the drug's clinical use in the hospital, we can see that the development of an excellent academic institution is far more than just chasing the latest trends. Closely following academic trends, strengthening academic exchanges, and promoting the construction of basic, clinical, and auxiliary departments are all indispensable factors in the development of diabetes diagnosis and treatment in my country.

【References】

Editor: Liu Yang and Zhao Na

Proofreading: Li Na, Li Yule, Dong Zhe, Li Huiwen

Producer: Wu Wenming

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