Can a mistake in insulin dosage be fatal? Scientific discussion of this scene in "The Long Season"

In the first episode of the hit suspense drama "The Long Season", the second male lead Gong Biao (Biaozi), who suffers from diabetes, took out the insulin syringe from the refrigerator and found that the "scale was wrong". This small detail attracted much attention at the end of the drama because of Biaozi's death. Many people speculated that Biaozi was murdered. How serious will the consequences be if you take too much or too little insulin? Let's start with the most basic principles.

Written by Guo Xiaoqiang (Hebei Institute of Physical Education)

Thirst, hunger, frequent urination, fatigue, weight loss... Humans have known the symptoms of diabetes for thousands of years, which can be summarized as "three mores and one less", that is, "drinking more, eating more, urinating more, and losing weight." In fact, the most direct impression is that urine becomes sweet, which is also the origin of the name "diabetes." Although diabetes has a long history and is very common, humans have been helpless against it for a long time. Although many so-called "magic prescriptions" and "good prescriptions" have appeared in history, they have all been proven to have little practical effect in the end. Even at the end of the 19th century, hunger therapy, which mainly reduces sugar intake, was still the best treatment option. In the popular TV series "The Long Season", the protagonist Biaozi is a diabetic who loves barbecue. Just imagine how cruel this treatment would be for him. And the effect was not good.

It wasn't until the advent of insulin that diabetes treatment underwent a fundamental change.

01

Discovery and application of insulin

In 1889, two German researchers, Oskar Minkowski and Joseph von Mering, performed a total pancreatectomy on a dog. After the operation, the dog developed symptoms of diabetes, such as increased blood sugar, and died soon after. This phenomenon shows that there is a close relationship between pancreatic destruction and the occurrence of diabetes. In 1910, British physiologist Sir Edward Albert Sharpey-Schafer gave his own explanation for this. He proposed that the pancreas can secrete a substance that controls blood sugar, and the lack of this substance is the cause of diabetes. He invented the word "insulin" to name this magical substance that controls blood sugar, that is, insulin. In this case, it means that supplementing insulin will be able to effectively solve the problem of diabetes. Unfortunately, many researchers have tried to obtain a certain amount of insulin from the pancreas, but all failed.

In 1920, the young Canadian doctor Frederick Grant Banting learned about the current status of insulin development and decided to challenge the difficulty of insulin extraction. He read the relevant literature and keenly realized that he could close the pancreatic duct first to cause necrosis of the pancreatic exocrine tissue, which would reduce the secretion of trypsin and effectively prevent insulin from being degraded before successful extraction! Although he had the idea, Banting himself lacked the necessary experimental facilities, so he sought cooperation from John Macleod, a scientist in the field of sugar metabolism. Macleod agreed with the suggestion, but he was preparing to travel at the time, so he assigned his assistant Charles Herbert Best to assist Banting in his work.

After many attempts and improvements, Banting and Best finally obtained a certain amount of relatively purified dog insulin. When they injected these purified substances into a dog with severe diabetes, a miracle occurred - the dog's blood sugar dropped rapidly, and various symptoms were relieved until it died due to lack of insulin. After returning from his trip, MacLeod immediately realized the clinical importance of this discovery and contacted the hospital to test the efficacy of insulin.

In January 1922, Thompson, a 14-year-old diabetic boy at Toronto Hospital in Canada, became the first patient to receive insulin treatment. Although the treatment effect was different from that of animal experiments, the overall effect was still satisfactory. This result caused a huge sensation and gave many diabetics hope for treatment. Subsequently, MacLeod invited biochemist James Collip to further improve the insulin extraction process, on the one hand to increase production to meet the needs of more patients, and on the other hand to improve insulin purity, reduce clinical adverse reactions, and improve clinical effects. Soon, animal insulin such as pigs and cattle was successfully extracted, and more and more diabetics could use insulin treatment. The crystalline artificial insulin that my country first synthesized in 1965 was bovine insulin.

The discovery and application of insulin has greatly improved the treatment of diabetes and is a milestone in the history of medicine. Banting and MacLeod also shared the Nobel Prize in Physiology or Medicine the following year (1923) for their discovery of insulin. Banting also became the youngest winner of the award in history (32 years old). The discovery of insulin is of great significance and indeed deserves the Nobel Prize. However, why did these two people win the prize? Controversy arose, and in the end Banting gave half of the prize money to Best, and MacLeod gave half of the prize money to Collip.

02

Development and improvement of insulin

Since the 1920s, the clinical demand for insulin has been increasing day by day, and supply shortages have inevitably occurred. At that time, insulin production mainly used the pancreas of cows or pigs, and the insulin content in the pancreas was extremely low, making it extremely expensive. Even in the 1980s, the pancreases of 23,500 animals were only enough to provide insulin for 750 diabetic patients for one year, which was prohibitive for diabetic patients from low-income families.

In the 1970s, the emergence of genetic engineering technology fundamentally changed the production of a variety of drugs, including insulin. In 1978, researchers at Genentech in the United States integrated the human insulin gene into the E. coli genome and used E. coli to produce human insulin. Because E. coli reproduces quickly and is easy to operate, it can be engineered for production. In a short period of time, the output of insulin was greatly increased, the cost was greatly reduced, and the price also dropped rapidly. Revolutionary technology gradually replaced traditional preparation methods, and genetically engineered insulin entered the homes of ordinary people and became a daily medication for most diabetic patients. (Thanks to genetic engineering, otherwise how could Biaozi afford insulin?)

The widespread use of insulin has also brought about rapid development in many aspects. Since the 1980s, researchers have no longer simply focused on the therapeutic effects of insulin, but have begun to consider aspects such as patients' daily life, lifestyle, and comfort in combination with the requirements of "long-term medication", thus promoting the rapid development of insulin dosage forms. Insulin pens and inhalable insulin and other products have been launched one after another, greatly facilitating patients.

Two types of pre-filled insulin pens. 丨Source: Wikipedia

03

How Insulin Works

After insulin is secreted into the blood (or exogenous insulin is injected into the body), it will be transported throughout the body. When it encounters effector cells (called "target cells"), it combines with molecules called "receptors" on the cell surface to initiate a variety of metabolic reactions in the cell. One of them is to accelerate the decomposition of glucose, increase glucose storage, or convert glucose into fat - so long-term use of insulin may cause weight gain (it is said that Brother Biao weighs 160 pounds) - ultimately achieving the purpose of lowering blood sugar.

Lack of insulin will disrupt the glucose balance in the body, causing blood sugar to rise and causing a series of damage to the body. There are two types of insulin deficiency. One is absolute deficiency, in which the body completely loses the ability to produce insulin. This is called type 1 diabetes, which is a hereditary disease. Patients develop the disease early, so it is also called juvenile diabetes. The other is relative deficiency, which means that the body can produce a certain amount of insulin, but the binding effect of insulin to the receptor is reduced, or there are other reasons that weaken its ability to lower blood sugar. This situation is called type 2 diabetes. Patients develop the disease late and usually have a certain genetic tendency. It is also called adult diabetes.

The therapeutic effects of insulin vary depending on the type of disease. Patients with type 1 diabetes are usually insulin-dependent for life, while patients with type 2 diabetes mainly need to increase insulin sensitivity.

There are many types of insulin currently used clinically, and their existence time in the body and the time they take effect vary greatly:

Rapid-acting insulin begins to work within 15 minutes of use, but its effects only last 2 to 4 hours.

Short-acting insulin (also called regular insulin) takes a little longer to take effect in the body (30 minutes) and lasts a little longer (3-6 hours) than rapid-acting insulin.

Long-acting insulin usually takes effect 2-4 hours after use, but can last for 24 hours, so it can meet the insulin needs of the whole day. Using long-acting insulin in the morning or before bed can control blood sugar levels throughout the day.

Ultra-long-acting insulin usually takes effect after 6 hours and can last for 36 to 42 hours. Another major difference between it and long-acting insulin is that it has no concentration peak (the efficacy is relatively stable), which can effectively reduce the risk of hypoglycemia.

In addition to the commonly used injectable insulin, there is also inhaled insulin, which falls into the range of rapid-acting or short-acting insulin (lasting about 3 hours).

Daily use usually consists mainly of long-acting insulin or ultra-long-acting insulin, with short-acting insulin used in combination.

For patients with type 1 diabetes and some patients with type 2 diabetes who use insulin for a long time, a small wearable insulin pump is a convenient option that can provide continuous doses of rapid-acting insulin. Currently, an automatic insulin delivery system has been developed that combines an insulin pump with a continuous blood glucose monitor to sense changes in blood glucose levels in a timely manner and adjust insulin dosage accordingly, which is more conducive to accurate blood glucose control.

Questions for consideration

What kind of diabetes does Biaozi have?

04

Insulin misuse

Insulin is good news for diabetic patients, but improper use may also have serious consequences.

The main purpose of insulin is to lower blood sugar, that is, the amount of glucose in the blood. Glucose is an extremely important energy substance. Too much is harmful, but too little can also cause problems. Therefore, the two most common misuses are insufficient insulin or excessive insulin.

How much insulin should a person take? We usually test the blood sugar-lowering effect by "starting from less to more, gradually increasing", and finally get a more suitable concentration range.

Why did Biaozi take insulin from the refrigerator? Because insulin is a protein with poor in vitro stability and usually needs to be stored in the refrigerator. If it is not stored properly, it is easy to cause a decrease in efficacy, and long-term use can easily delay the disease. In addition, insufficient dosage can easily lead to unsatisfactory blood sugar control effects, which is not conducive to controlling the disease.

By the way, injecting insulin at low temperatures can easily cause discomfort, so generally speaking you should take it out of the refrigerator a little earlier and inject it slowly.

If you inject too little, the disease won't be cured. Will it be okay if you inject a little more? It is indeed very common to inject too much. Due to calculation errors, repeated injections or incorrect dosage forms, excessive insulin enters the body, causing blood sugar levels to fall below the minimum value, which can also lead to a series of adverse consequences. Mild symptoms include dizziness, hunger, fatigue, rapid heartbeat, lack of concentration, sweating, pale skin... Severe symptoms include coma, loss of sense of direction, and epileptic seizures. At this time, carbohydrates should be supplemented in time to relieve the symptoms of hypoglycemia. If the condition is serious, seek medical attention in time. Long-term use of insulin without a good grasp of the dosage may have the side effect of hypoglycemia.

If Biaozi's insulin was tampered with, could it be that he injected too little or too much? But in either case, it would take more than one tampering to produce any consequences, and it is unlikely to directly cause a car accident.

References

[1] Vecchio I, Tornali C, Bragazzi NL, Martini M. The Discovery of Insulin: An Important Milestone in the History of Medicine. Front Endocrinol (Lausanne), 2018,9:613.

[2] FDA. 100 Years of Insulin (https://www.fda.gov/about-fda/fda-history-exhibits/100-years-insulin)

[3] Doskicz J. The 6 Types of Insulin: A Guide to Regular, Short, and Long-Acting Insulins(https://www.goodrx.com/classes/insulins/insulin-types-how-to-use)

[4] Insulin Overdose (https://www.diabetes.co.uk/insulin/insulin-overdosage.html)

[5] Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev, 2018, 98(4):2133-2223.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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