In the first episode of the hit suspense drama "The Long Season", Gong Biao (彪子), the male number two with diabetes, took out the insulin syringe from the refrigerator and found that "the scale is wrong". This small detail attracted much attention at the end of the play because of Biaozi's death, and many people speculated that Biaozi was murdered. How serious will the consequences be if insulin is beaten more or less? Let's start with the basics.
Written by | Guo Xiaoqiang (Hebei Institute of Physical Education)
Thirst, hunger, urinating too much, fatigue, wasting... Human beings have known about diabetes symptoms for thousands of years, which can be summarized as "three more and one less", that is, "more drinking, more food, more urine, weight loss". In fact, everyone's 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, human beings have been helpless against it for a long time, and although there have been many so-called "magic remedies" and "good remedies" in history, they have been proved to have little practical effect. Even at the end of the nineteenth century, the hunger treatment based on reducing sugar intake was the best treatment - in the hit drama "The Long Season", the protagonist Biao Zi is a diabetic who loves barbecue, think about how cruel this treatment should be to him - and it is not very effective.
It wasn't until the advent of insulin that there was a fundamental shift in diabetes treatment.
01
Discovery and application of insulin
In 1889, two German researchers, Oskar Minkowski and Joseph von Mering, performed a total pancreatic resection in dogs, after which the dog developed diabetic symptoms such as elevated blood sugar and died soon after. This phenomenon suggests a strong association between pancreatic destruction and the development of diabetes. In 1910, British physiologist Sir Edward Albert Sharpey-Schafer gave his own explanation, proposing that the pancreas can secrete a substance that controls blood sugar, and the lack of this substance is the cause of diabetes. He coined the word "insulin" to name this miracle substance that controls blood sugar, or insulin. That being the case, it means that supplementing with insulin will be able to effectively address diabetes. Unfortunately, multiple researchers have failed to try to get a certain amount of insulin from the pancreas.
In 1920, Frederick Grant Banting, a young Canadian physician, learned about the development of insulin and decided to challenge the problem of insulin extraction. He read the relevant literature and keenly realized that the pancreatic duct can be closed first, so that the exocrine tissue of the pancreas dies, which can reduce trypsin secretion and effectively avoid the degradation of insulin before successful extraction! The idea was, but Banting himself lacked the necessary experimental facilities, so he approached John Macleod, a scientist in the field of glucose metabolism, for collaboration. MacLeod accepted the suggestion, but he was preparing to travel, so he assigned his assistant, Charles Herbert Best, to assist Banting.
After many attempts and improvements, Banting and Best finally obtained a certain amount of purified dog insulin. When they injected these purifiers into a dog with severe diabetes, a miracle worked—the dog's blood sugar dropped rapidly, symptoms eased, and eventually died when no insulin was available. Upon returning from a trip, McLeod immediately realized the clinical importance of this discovery and immediately contacted the hospital to test the efficacy of insulin.
In January 1922, Thompson, a 14-year-old diabetic boy at a hospital in Toronto, Canada, became the first patient to receive insulin therapy. Although the treatment effect differs from animal testing, the overall effect is satisfactory. This result caused a huge sensation and made many diabetics see the hope of treatment. Subsequently, MacLeod invited biochemist James Collip to further improve the insulin extraction procedure, on the one hand, increase the production to meet the needs of more patients, on the other hand, improve the purity of insulin, reduce clinical adverse reactions, and improve clinical results. Soon, animal insulin such as pigs and cattle has been successfully extracted, and more and more diabetic patients can be treated with insulin. The crystalline artificial insulin first synthesized by Continental in 1965 is the choice of bovine insulin.
The discovery and application of insulin greatly improved the treatment of diabetes and was a landmark event in the history of medicine, and Banting and MacLeod also shared the Nobel Prize in Physiology and Medicine the following year (1923) for "discovering insulin", and Banting became the youngest winner (32 years old) in the history of the award. The discovery of insulin is significant and indeed worthy of the Nobel Prize, but why did these two win the award? Controversy ensued, and Banting eventually gave half of the prize money to Best and McLeod gave half of the prize money to Collip.
02
Development and improvement of insulin
Since the 20s of the 20th century, the clinical demand for insulin has been increasing day by day, and there is inevitably a shortage of supply. At that time, insulin production mainly used the pancreas of cattle or pigs, and the insulin content of the pancreas was extremely low, making it extremely expensive. Even in the '80s, the pancreas of 23,500 animals was only enough for 750 diabetics to use insulin for a year, putting diabetics off from low-income families.
In the 70s of the 20th century, the emergence of genetic engineering technology fundamentally changed the production of a variety of drugs, including insulin. In 1978, Genentech researchers integrated the human insulin gene into the E. coli genome, using E. coli to produce human insulin. Due to the rapid reproduction of E. coli, the simple operation, and the realization of engineering production, the production of insulin has been greatly increased for a while, the cost has been greatly reduced, and the price has also fallen rapidly. Revolutionary technology gradually replaced traditional preparation methods, and genetically engineered insulin entered ordinary people's homes and became the daily medication of most diabetics. (Thanks to genetic engineering, how else could Biao Zi afford insulin?) ）
The ubiquitous use of insulin has also led to rapid development in many ways. Since the 80s, researchers have no longer simply focused on the effect of insulin therapy, but combined with the requirements of "long-term medication", they began to consider the patient's living, lifestyle and comfort, thereby promoting the rapid development of insulin dosage forms, and products such as insulin pens and inhalable insulin have been launched one after another, which greatly facilitates patients.
Two types of prefilled insulin pens. Source: Wikipedia
03
Mechanism of action of insulin
After insulin is secreted into the bloodstream (or exogenous insulin is injected into the body), it is transported throughout the body, and when it encounters effector cells (called "target cells"), it binds to molecules called "receptors" on the surface of the cell to initiate a variety of metabolic reactions in the cell. One of them is to accelerate glucose breakdown, increase glucose storage, or convert glucose into fat — so long-term use of insulin may lead to weight gain (said to be 160 pounds) — and ultimately lower blood sugar.
Lack of insulin will disrupt the glucose balance in the body, causing blood sugar to rise, causing a series of damage to the body. There are two types of insulin deficiency, one is absolute deficiency, the body completely loses the ability to produce insulin, this is called type I diabetes, belongs to a genetic disease, patients have early onset, so it is also called juvenile diabetes; The other is relative deficiency, that is, the body can produce a certain amount of insulin, but the binding effect of insulin and receptors is reduced, or for other reasons, its ability to lower blood sugar is weakened, this situation is called type II diabetes, patients have a late onset, usually have a certain genetic predisposition, also known as adult diabetes.
Depending on the type of disease, the therapeutic effect of insulin also varies. Patients with type I diabetes are usually lifelong insulin-dependent, while type II patients mainly require increased insulin sensitivity.
There are many types of insulin currently used clinically, and their presence in the body and the duration of their action are also quite different:
Rapid-acting insulin, which begins to work 15 minutes after use, but the effect lasts only 2 to 4 hours.
Short-acting insulin (also known as regular insulin) has a slightly longer onset of action (30 minutes) and duration (3-6 hours) than rapid-acting insulin.
Long-acting insulin, which usually takes effect 2-4 hours after use, but can last for 24 hours, can meet the need for insulin throughout the day, and long-acting insulin in the morning or before bedtime can control blood sugar levels throughout the day.
Ultra-long-acting insulin, which usually takes effect in 6 hours and lasts for 36 to 42 hours, is also different from long-acting insulin in that there is no peak concentration (the drug effect is relatively stable), which can effectively reduce the risk of hypoglycemia.
In addition to commonly used injectable insulin, there are also inhaled insulin, which are in the range of rapid-acting or short-acting insulin (lasting about 3 hours).
Routine use is usually based on long-acting insulin or ultra-long-acting insulin, while short-acting insulin is used in combination.
For type I diabetic patients and some type II diabetic patients who have been using insulin for a long time, small wearable insulin pumps are a convenient option that provides a continuous dose of rapid-acting insulin. At present, an automatic insulin delivery system has been developed, which combines an insulin pump with a continuous glucose monitor, which can detect changes in blood glucose content in time and adjust the amount of insulin accordingly, which is more conducive to precise blood sugar control.
Question to think about: What kind of diabetes does Biaozi have?
04
Insulin misuse
Insulin is a boon for diabetics, but improper use can also have serious consequences.
The main purpose of insulin is to lower blood sugar, that is, the amount of glucose in the blood, and glucose is an extremely important energy substance, more is harmful, but too little can also be a problem. Therefore, two common types of misuse are insulin insufficiency or overdose.
How much insulin should a person really take? We usually take a "less to more, gradually increasing" method to detect the hypoglycemic effect, and finally obtain a more suitable concentration range.
Why did Biao Zi take insulin from the freezer? Because insulin is a protein, it is less stable in vitro 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 application is easy to delay the disease. In addition, insufficient dosage can also easily cause unsatisfactory blood sugar control effect, which is not conducive to controlling the disease.
By the way, low-temperature insulin injections are easy to be uncomfortable, so generally speaking, take it out of the refrigerator a little in advance and slowly hit it again.
If you fight less, you can't cure it, and if you fight a little more, is it okay? It is indeed common to fight too much. Excessive insulin entering the body due to miscalculations, repeated injections or incorrect dosage forms can also lead to a series of adverse consequences. Dizziness, hunger, fatigue, rapid heartbeat, lack of concentration, sweating, pale skin... Severe cases include coma, loss of direction, and seizures. At this time, carbohydrates should be supplemented in time to relieve symptoms of hypoglycemia, and if it is serious, seek medical attention in time. Long-term use of insulin, if you do not grasp the amount well, may have the side effect of hypoglycemia.
If Biaozi's insulin is passive, is it possible to hit less, or maybe to hit more? But in either case, to have consequences, you need to move your hands and feet more than once, and it is unlikely to directly cause a car accident.
bibliography
[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 Popular Science China Starry Sky Project
Produced by: Science Popularization Department of China Association for Science and Technology
Executive producers: China Science and Technology Press Co., Ltd., Beijing Zhongke Galaxy Culture Media Co., Ltd
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