Wang Shuxian is a senior diabetologist and nephrologist in China. In 1937, he completed the earliest clinical study of diabetes in China with a large number of cases using 405 cases of diabetes at Peking Union Medical College Hospital as samples. This article introduces his research and gives a corresponding review to trace the history of diabetes in China and review the work of the academic predecessors.

Author: Gu Xiaoyang and Li Naishi

1. Biography of Wang Shuxian

Wang Shuxian (1904-1985), a native of Shanghai, graduated from Peking Union Medical College in 1930 with a doctorate in medicine. From 1930 to 1942, he worked as an assistant professor, lecturer, and associate professor of internal medicine at Peking Union Medical College. In early 1942, Peking Union Medical College was forced to close due to the fall of Peking. Wang Shuxian went to Peking Qingyuan Hospital to practice medicine, and served as director of internal medicine and acting dean. After liberation, Wang Shuxian worked for a long time at Peking University School of Medicine (later renamed Peking Medical College, Peking Medical University, and now Peking University School of Medicine), serving as a professor of internal medicine, director of the Department of Medicine, director of the Institute of Clinical Medicine, director of the Department of Internal Medicine at Peking University First Hospital, and director of the Nephrology Research Laboratory, until he died of a sudden heart attack in 1985[1].

Wang Shuxian was the first chairman of the Chinese Society of Nephrology and the editor-in-chief of the Chinese Journal of Nephrology. Although the medical community now commemorates him as a nephrologist, his early medical research also involved diabetes, tuberculosis, calcium and phosphorus metabolism, and his research on diabetes was particularly outstanding.

2. Wang Shuxian and China's earliest clinical study on diabetes

In 1937, Wang Shuxian published the earliest clinical study on diabetes in China, which was also the only one with a large number of cases before 1949. He conducted a retrospective case analysis of 405 cases of diabetes (including 347 Chinese patients) who were hospitalized in the Department of Internal Medicine of Peking Union Medical College Hospital since its establishment. The data were detailed and the analysis was meticulous. On the basis of horizontal comparison with foreign studies of the same period, the author summarized the disease characteristics and treatment points of diabetes in China. It can be said to be a culmination of diabetes research in my country at that time [2].

The study was titled "Diabetes Mellitus: An Analysis of 347 Cases (Chinese Inpatients)" and was published in two parts in the English version of the Chinese Medical Journal. The first part mainly summarizes the prevalence, symptoms, laboratory tests and complications, while the second part focuses on treatment and prognosis. The following article will introduce and comment on this paper. The article begins by pointing out that studies have shown that genetic factors play an important role in the development of diabetes, so the incidence, severity and manifestations of the disease vary by race. Regarding the situation of diabetes in China, previous researchers have different impressions based on their own observations, and there is no unified conclusion.

In order to understand the basic situation of diabetes in China, the author collected and analyzed the medical records of all diabetic inpatients admitted to Peking Union Medical College Hospital from 1921 to 1935. Due to the limited number of cases, the author emphasized that the conclusions drawn from this report may not be applicable to the whole of China, but hoped to arouse more medical colleagues to pay attention to and join China's diabetes research.

3. Analysis of 347 Chinese Diabetes Hospitalized Patients: Observations and Reflections of Early Chinese Diabetologists

The first part of the article is a basic situation analysis. The author introduces the data source, the incidence of diabetes in hospitalized patients, gender and age distribution, social status, and nutritional status. According to statistics, among the inpatients at Union Hospital, the prevalence of diabetes in Chinese is 0.8%, and that in foreigners is 0.89%. At that time, foreign studies have suggested that diabetes often occurs in wealthy and obese people. The author pointed out that 22% of the patients in this study lived in private wards and should belong to the wealthy class, while there were also patients with good economic conditions who wanted to save hospitalization fees in public wards, so it was speculated that at least 1/4 of the patients belonged to the wealthy class. According to the doctor's physical examination impression at admission, the patients were roughly divided into four categories: thin, malnourished, well-nourished, and obese. 26% of Chinese male and female patients were obese and 48% were well-nourished. Considering that most patients had been ill for a period of time when they were admitted to the hospital and had lost weight, the actual proportion of obese patients should be higher than this. Previously, some doctors in Chinese medical journals debated whether diabetes was less common in China than in other countries, and based on their personal experience in diagnosis and treatment, they gave the impression that most Chinese patients with diabetes were relatively wealthy [3,4,5]. Wang Shuxian was the first to verify, based on statistical data, that diabetes was not uncommon in China and that most of them came from relatively wealthy social classes.

The second part is the symptoms of diabetes. This part especially reflects the author's careful observation and analysis of the disease as a clinical physician. The author lists the symptoms according to the frequency of occurrence and compares them with foreign data. Polydipsia, polyphagia and polyuria are the most common symptoms, but the ratio is lower than that shown in foreign studies. The author's analysis does not rule out that the doctor who collected the medical history at the time of admission did not ask the medical history in detail, but considering that the ratio of asymptomatic patients in the study is much higher than the research data of other countries, it is more likely to indicate that Chinese people have a milder condition when they suffer from diabetes. Pain and numbness are quite common in Chinese diabetic patients, and itching is common in female patients. Lethargy and coma, which are often reported abroad, are not common in Chinese patients, and both are almost always accompanied by acute infection. Asymptomatic patients account for 20%~30% of the study population, which is significantly higher than the proportion in foreign studies. The author pointed out that this situation and the low incidence of ketoacidosis may also indicate that Chinese people have a milder condition when suffering from diabetes.

The third part is laboratory examination. The author analyzed the examination items such as urine volume, urine sugar, urine ketone bodies, urine protein, glucose tolerance test, blood cholesterol, basal metabolic rate and respiratory quotient. Except for the last two examinations, which were too few, Union Hospital conducted relatively complete laboratory examinations on most patients at the time. The author emphasized the importance of laboratory examinations. Urine sugar is an extremely important indicator, and urine ketone bodies indicate that the disease is more serious. Blood sugar levels are not completely consistent with the severity of the disease, but there are significant differences in blood sugar levels between patient groups with different severities. The author also summarized the significance of the glucose tolerance test, pointing out that patients with severe conditions have earlier, higher peaks and more sustained increases in the glucose tolerance curve than patients with mild conditions.

The fourth part discusses complications of diabetes . The author lists 21 diseases in the table by frequency of occurrence, including obesity, arteriosclerosis, hypertension, skin infection, tuberculosis, ketosis, heart disease, diabetic nephropathy, syphilis, cataracts, malignant tumors, nephritis, diabetic coma, pituitary and thyroid diseases, gangrene, etc. He pointed out that diabetes is usually a chronic disease that can occur in all age groups, so all diseases may occur in diabetic patients, but some diseases are more common in diabetic patients and have a particularly great impact on diabetes, and can be considered as complications unique to diabetes.

Although ketosis and coma are not the most frequent complications, the author still analyzed them, pointing out that, to be precise, they are the results of diabetes rather than complications. They often occur with some complications or are induced by hunger or sudden withdrawal of insulin. Ketoacidosis coma is relatively rare in China, which may be another indication that Chinese diabetic patients have milder conditions. The relationship between arteriosclerosis, hypertension, obesity and diabetes is unclear, but all three are more common in diabetic patients than in non-diabetic patients.

Gangrene in Chinese patients is often dry and occurs less frequently than in foreign patients. The author believes that this may be because Chinese patients are younger. If these diabetic patients live longer, the number of cases of arteriosclerosis and gangrene may increase. Skin suppurative infections, including furuncles, carbuncles, and abscesses, are common in Chinese patients. The author pointed out that his colleague Mills found the same problem in a survey conducted 10 years ago [6]. The reason why Chinese patients have a significantly higher rate of skin infections than foreign patients is probably because the poor in China lack water and bathing facilities and cannot keep their skin clean. Complications related to poverty include not only skin infections, but also tuberculosis infections that cannot be ignored.

The authors point out that although tuberculosis is now quite rare among diabetics in the United States, it is still the most common complication of diabetes in China. Tuberculosis makes the treatment of diabetes more complicated - TB patients need adequate nutrition, while diabetes requires strict dietary restrictions. Like other infections, tuberculosis also worsens the patient's blood sugar status, which further restricts the patient's food intake and ultimately reduces the possibility of recovery from tuberculosis. This vicious cycle is undoubtedly a treatment problem facing doctors in old China, where people's health conditions were poor.

IV. Dietary treatment of diabetes in China during the Republic of China period

The fifth part of the article "Analysis of 347 Chinese Inpatients with Diabetes" discusses the issue of treatment. The collection of research cases began in 1921, and insulin was launched in 1923, so insulin therapy was not included in the treatment in the first two years.

The author first discussed dietary therapy. He pointed out that the principles of dietary therapy in Union Hospital have changed a lot over the years, and are basically consistent with the academic views prevalent in other parts of the world. In the 14 years from 1921 to 1935, Union Hospital successively implemented several therapies, including starvation therapy (1921 to 1922), high-fat diet (about 1922 to 1928), moderate high-fat diet (1928 to 1930), metabolic balance diet (1930 to 1934), high-carbohydrate, low-fat diet (1934 to 1935, used only in a few cases).

The author concluded that it is difficult to say which method is the most effective because the different therapies were not used at the same time. In his opinion, the effects of these dietary therapies are equally good, but each has its own advantages and disadvantages. Starvation therapy is very inconsistent with physiological laws and has been basically abandoned, but it can effectively eliminate urine sugar in a short period of time. High-fat diets are difficult to swallow, and there is also the problem of malabsorption when eating large amounts. The emerging metabolic balance diet attempts to adjust the proportion of protein, fat and carbohydrates in the patient's food to achieve metabolic balance and avoid the production of urinary ketone bodies, but this program requires a longer adjustment time.

Given that the condition of most Chinese patients with diabetes is relatively mild, there is no need to choose such a strict and time-consuming method. The closer the carbohydrate content in the diet is to normal, the easier it is for patients to follow. However, whether high carbohydrates are harmless to patients or even cause harm in the later stages requires more clinical experience to verify. Since diabetes experts in the United States, Germany, Britain and other countries also had different opinions on dietary treatment at the time, Chinese doctors needed to independently explore unique dietary guidance suitable for Chinese diabetic patients [7]. Based on clinical practice, the author summarized the following experience for the management of hospitalized diabetic patients: a relatively high-carbohydrate basic diet is given upon admission, maintained for 2 to 3 days to roughly understand the patient's tolerance to carbohydrates. Afterwards, every effort should be made to turn the patient's urine sugar negative.

For patients with mild or less severe conditions, 40-60 g of carbohydrates, 1 g of protein per kilogram of body weight and enough fat are given every day so that the total calories can meet the patient's basal metabolic needs. Based on this diet, the patient can turn urine sugar negative in about 7-10 days. If after a few days of observation, it is found that the course of treatment may be extended or the patient needs to control urine sugar more quickly, sufficient insulin treatment should be gradually increased to eliminate urine sugar and reduce blood sugar to normal levels. After blood sugar returns and remains normal for about a week, the diet is increased by 10-15 g of carbohydrates every 4 days, and other foods remain unchanged. For any patient, the carbohydrate intake of the diet should be gradually increased to the range that the patient can tolerate. In theory, carbohydrates should be gradually increased until sugar appears in the patient's urine again, and then reduced by 20%, and this value is used as a long-term carbohydrate intake. In practice, if carbohydrates have been increased to 150-200 g and the patient has adapted well, he or she can also be discharged in this way. The author emphasizes that in any case, carbohydrates should be increased to as high a level as the situation allows, so that the patient's compliance is better.

The reason why Wang Shuxian introduced the practical experience of adjusting diet in such detail is inseparable from the situation of diabetes treatment in China at that time and his habit of focusing on clinical observation and summary. Modern medical diabetes diet treatment requires patients to persist in managing, weighing, and planning their own diet, which is particularly difficult for Chinese people who "consider diet to be one of the greatest joys in life" [8]. Wang Shuxian once lamented that several of his patients "could not follow the diet, or did not receive long-term treatment and did not see results". He once wrote a special article summarizing simple diet therapy suitable for outpatient clinics, made simple recipes based on common Chinese food types, and listed several foods that can be converted in equivalent amounts to prepare for changing tastes [9].

5. Insulin treatment of diabetes in China during the Republic of China period

After the dietary therapy, the author also devoted a large section to the introduction of insulin therapy. Peking Union Medical College Hospital began using insulin in July 1923[10]. By 1935, a total of 110 patients had used the drug, accounting for one-third of the inpatients with diabetes. The final follow-up showed that only 9% of the patients needed long-term use of insulin, and more than two-thirds of the patients did not need the drug at all, which was much lower than the proportion reported abroad.

In 1927, Mills first summarized the experience of insulin use in the Internal Medicine Department of Union Hospital, and proposed that "two Chinese diabetic patients died of insulin treatment within one month, which strongly suggested that Chinese people may be particularly sensitive to this drug." Wang Shuxian found that among all the deaths, only these two patients died of severe hypoglycemia coma after using lower insulin doses (4 U and 5 U). He analyzed that both patients were extremely thin, weighing less than 40 kg, and at the same time suffered from severe tuberculosis, which may be very sensitive to hypoglycemia shock. Based on the research data, he concluded that the probability of hypoglycemia reaction in Chinese patients using insulin is not higher than that of foreign data, and the inference that Chinese people are particularly sensitive to insulin has not been confirmed in this study. He emphasized that any patient should be paid attention when using insulin, especially when the dose is large and frequent. But the reason for cautious administration is that most Chinese diabetic patients have milder conditions and require smaller insulin doses, not because Chinese patients are more sensitive to insulin.

In terms of experience with insulin use, the authors concluded that multiple small doses are safer and, in some cases, more effective than single large doses. When insulin is given repeatedly, the patient's blood sugar and urine sugar levels must be carefully and frequently monitored. No matter how small the insulin dose is, the patient's blood sugar and urine sugar levels must be clearly determined before medication. Physicians must avoid falling into a situation where, after an injection of insulin, they are confused about whether the patient has a diabetic coma or a hypoglycemic coma. The authors concluded that the indications for the use of insulin include: (1) severe diabetes with carbohydrate tolerance of less than 40 to 60 g; (2) diabetes with internal and surgical complications; and (3) diabetic coma and acidosis. Insulin should not be used if these three conditions are not met.

It is important to emphasize that insulin, as a brand-new biological agent at the time, entered clinical trials in China at about the same time as Western countries such as the United States and the United Kingdom. This means that at the time, Chinese clinicians did not have clear and mature experience to draw on regarding the characteristics, usage, dosage, indications, etc. of the drug. Against this historical background, the precautions and guidelines for the use of insulin summarized by the author appear particularly insightful.

In the treatment section, the author also specifically mentioned a problem with Chinese characteristics. There has been a long-standing rumor among the Chinese people that eating raw pancreas can cure diabetes. The author concluded that the method of eating raw pancreas was tried on several patients, but no obvious effect was seen [11].

6. Prognosis and characteristics of diabetes in China during the Republic of China period

Part 6 of the article summarizes the issue of disease prognosis. About 11.8% of the 347 Chinese patients died during hospitalization or shortly after discharge, and complications were an important cause of death. Infection was the most common fatal complication, accounting for 1/3, and coma was the second, accounting for 1/4, which was very different from the results of studies in the United States during the same period. According to a report by American diabetics Joslin, vascular sclerosis is an important cause of death among American diabetic patients, while coma only accounts for 4%. In response to this difference, the author analyzed that diabetic patients are particularly prone to infection, and due to the extremely high infection rate of Chinese patients, they often die at an age before vascular sclerosis occurs.

In the following section, the author clearly emphasizes the chronic nature of diabetes - it is incurable, but after treatment, patients may be able to regain some ability to metabolize carbohydrates. The author talks about the severity and classification of the disease at the end of the prognosis chapter. He pointed out that there is currently a lack of appropriate disease classification for diabetes. Many factors, such as blood sugar, urine sugar, glucose tolerance curve, blood lipids, degree of ketosis, etc., affect the classification. Based on treatment response and other indicators, the author proposed that all cases can be divided into four categories: latent, mild, moderate, and severe diabetes.

The last part of the paper is the summary and conclusion. The author once again lists the important conclusions of the previous article in paragraphs, concluding that the condition of Chinese diabetic patients is milder than that of Western patients. As for the prevalence of diabetes, it is difficult to draw a final conclusion. It seems that the prevalence in China is lower than that in other countries, but this may be because the general public knows nothing about this disease and does not pay attention to it. For doctors and patients, other medical problems may be more urgent at this stage. However, according to the experience of Peking Union Medical College Hospital, diabetes patients in China are not uncommon compared with those abroad.

"Diabetes: Analysis of 347 Chinese Hospitalized Patients" is an extremely outstanding and significant paper. First, it provides a comprehensive and profound summary of the diagnosis and treatment of Chinese diabetic patients, so all diabetes-related data are reflected in this paper, and even rare side effects such as insulin allergy are mentioned in this paper. Secondly, in an era when there were many different opinions on dietary treatment, Wang Shuxian did not blindly follow foreign views, but summarized a set of effective diabetes dietary plans based on the experience of Union Hospital. Third, he explored unique experience in the use of the new drug insulin, and overturned Professor Mills's erroneous views on Chinese diabetic patients with his own detailed observations and rigorous reasoning. Finally, the paper also made a very concise classification of diabetes according to the needs of treatment, which had a huge impact on the subsequent diabetes treatment in China.

In the 1920s and 1930s, Wang Shuxian's main research direction in the endocrine metabolism and nephrology team at Union Hospital was diabetes, and his achievements were remarkable. Although he later devoted his main energy to the study of nephrology, he still trained diabetes experts such as Shi Manshu, Gao Yan, and Qian Rongli, making important contributions to the development of diabetes in my country.

【References】

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[2]Shu-Hsien Wang . Diabetes mellitus an analysis of 347 cases (Chinese inpatients): part I. incidence symptoms, examination, and complications[J]. Chin Med J, 1937,51(1):9-32.

[3]Richard Smyth. The pathology of diabetes mellitus[J]. China Med Mission J, 1901,15(1):20-23.

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[5]Chun JWH. The influence of the Chinese diet on disease[J]. Chin Med J, 1925,39(2):1046-1045.

[6]Mills CA . Diabetes among the Chinese: danger of insulin usage[J]. Chin Med J, 1927,41(11):914-921.

[7]Blades M, Morgan JB, Dickerson JW. Dietary advice in the management of diabetes mellitus--history and current practice[J]. JR Soc Health, 1997,117(3):143-150.

[8] Translated by Cheng Hanzhang. Treatment of diabetes mellitus[J]. Nature, 1929, 4(8):705-710.

[9] Wang Shuxian. Simple and practical treatment for diabetes[J]. Chinese Medical Journal, 1935, 21(10): 1059-1070.

[10] Li Naishi. Medical record of the first case of diabetes treated with insulin in Peking Union Medical College Hospital in 1923[J]. Chinese Journal of Diabetes, 2015, 4(1): 56-57. doi: 10.3760/cma.j.issn.1674-5809.2012.01.016 .

[11] Zhang Xichun. On the causes and treatment of diabetes. Medical Journal[J]. 1929(47):50-52.

Editor: Liu Yang and Zhao Na

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

Producer: Wu Wenming

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