1922: “Take the initiative” against diabetes

  In the history of mankind’s struggle against diabetes, 1922 is a year to remember. In the early spring of that year, a group of diabetic patients gathered in Toronto, Canada. Many of this huge team were scrawny and full of sour stench. However, the “miracle” happened very quickly. Many people in the team, and even many dying people, soon regained their vitality after being injected with a magical potion.
  In the long history of fighting against diabetes, human beings have been at a disadvantage, until the advent of the magic agent-insulin, diabetic patients finally ushered in the dawn of changing their fate. The emergence of insulin has changed the relationship between human beings and diabetes from “resignation” to “active attack”.
  So, what kind of disease is diabetes? Why has mankind been helpless in the face of it for thousands of years? What exactly happened 100 years ago to bring about a major turning point in the relationship between humans and diabetes?
pre-insulin era

  Diabetes mellitus is a chronic metabolic disease with extensive incidence, which is directly characterized by elevated glucose levels in the blood, and often leads to various complications that are life-threatening. Conservatively estimated from a global scale, about 1 in 15 people will have diabetes.
  Although diabetes is a common chronic disease of modern people, it is not an exclusive disease of modern people. A simple account of diabetes is found on an ancient Egyptian papyrus about 3,500 years ago. More than 2,000 years ago, the ancient Greek doctor Apollonius named a disease whose main symptom is “excretion of excessive and sweet urine” Diabetes (that is, diabetes in English). The ancient Indians also formed the empirical understanding that “the urine often attracts ants and flies to judge the disease”.
  In ancient Chinese literature, there are also many records about diabetes. More than 2,000 years ago, the “Huangdi Neijing” was recorded in the “On Odd Diseases”, “The Emperor said: If there is a disease of the mouth, what is the name of the disease? . Not only the disease, but also the cause, which is attributed to the “overflow of five qi”. Liu Wansu, a medical scientist of the Jin Dynasty, recorded in the “Liu Shu of Hejian”: “If you drink a lot of water and urinate a lot, it is called diabetes. If you eat a lot but you are not hungry, and you lose weight because you urinate a lot, it is called Xiaozhong. If you are thirsty and drink water continuously, and your legs are thin and there is fat in the urine, it is called kidney Xiao.” This document also analyzes some of the causes: “People who are thirsty are due to unsuitable food and beverages, dry stomach, and gas. The liquid should not be declared calm, or it may consume the spirit, violate its degree, or due to serious illness, the yin qi is depleted and the blood is deficient, and the yang qi is strong and dry and hot.” Analysis of the etiology of diabetes: “Three thirsty people are all addicted to salty things for a long time, unbridled eating and drinking, and drinking too much. There are also young people who take Jinshiwan powder, accumulate food heat for a long time, and accumulate in the chest, the lower Jiao is deficient and hot, and the blood and qi cannot make stones. The heat is more dry than the stomach, so thirsty leads to drinking.”
  It can be seen from the above literature that the ancients believed that diabetes was related to living habits such as “long-term addiction to salty foods, unbridled food and excessive drinking”. This kind of understanding has a certain rationality. Even in contemporary times, long-term intake of high-carbohydrate foods and lack of exercise are still the main causes of diabetes. Therefore, ordinary people often call this disease a “rich and noble disease”. According to the modern classification of diabetes, diabetes known as “rich disease” mainly refers to type II diabetes. People with this condition have a reduced sensitivity to sensing the level of insulin in the blood, so they can neither activate the mechanisms that absorb excess glucose in the blood nor stop glucose synthesis, and therefore cannot regulate blood sugar levels in the body. Type 1 diabetes is primarily associated with an innate immune dysregulation that causes the body to fail to sense increases in blood sugar levels, or to apoptosis of beta cells in the pancreas, which prevents insulin production from starting.
  In the long ancient society, although people also adopted simple treatment methods such as controlling diet and strengthening exercise, on the whole, the ancient people’s understanding of diabetes was very limited. Until the beginning of the 20th century, the treatment of diabetes was not much better than it was thousands of years ago, and the only effective treatment was starvation therapy. Most of the severely ill diabetic patients died in the torture of polydipsia, thirst and weight loss.
  As can be seen from the name of insulin, this substance is related to the organ in the human body – the pancreas. The ancient Greeks had discovered the pancreas close to the stomach and small intestine, but it was unclear what role this organ played. In 1888, while conducting research on digestive physiology, Russian scientist Pavlov discovered the digestive function of pancreatic secretions. In 1889, when studying the specific digestive function of the pancreas, Feng Meilin and Minkowski of the University of Strasbourg found that the experimental dogs who had removed the pancreas had symptoms of polyuria and sweet urine (attracting a group of flies). Through quantitative research, they determined the relationship between the pancreas and diabetes. In 1901, American physician Opie further clarified the causal relationship between islets in the pancreas (the endocrine part of the pancreas) and diabetes.
  Since then, many doctors and scientists have tried to extract insulin directly from the pancreas. However, because the digestive enzymes secreted by acinar cells can destroy insulin, it is difficult to directly extract the active ingredient. More than ten years later, scientists still have not found an extraction method that meets both safety requirements and clinical efficacy.
Who is driving the turning point in history

  In 1989, a square in London Township, Ontario, Canada was named after Banting. In 1991, the World Health Organization and the International Diabetes Federation designated November 14 as “World Diabetes Day”, which is Banting’s birthday. These honors are in recognition of Banting’s outstanding achievements in extracting insulin in 1922. Before that, Banting was a general physician with little to do with scientific research.
  Banting was born in 1891 and attended the University of Toronto medical school in his youth. After the outbreak of the First World War, he went to the French front to become a military doctor. On the battlefield, Banting saved many wounded soldiers despite the artillery fire, and he was also injured in the battle, for which he won the Military Merit Cross.
  After the war, Banting, 28, first worked in a children’s hospital and soon opened a small clinic in London, Canada. Presumably not earning enough to support his family, he took a part-time job teaching students at a nearby university. While preparing for the class “Pancreatic Function and Glucose Metabolism”, he read a scientific literature on diabetes. From the literature, he learned that the duct from the pancreas to the duodenum will be blocked by stones, causing acinar cells to shrink and die, but the pancreatic islets will not be affected, nor will it cause diabetes. This phenomenon can also occur through ligation of the duct. The scientific literature directly sparked Banting’s imagination, and in his view, this was a plausible route to purify insulin from the pancreas. So, is it possible to ligate the pancreatic duct to cause the death of acinar cells and extract higher-purity insulin from the remaining islet cells?
  With such thoughts and excitement, one day in November 1920, after being recommended by a friend, Banting walked into the office of Macleod, a British physiologist, head of the Department of Physiology at the University of Toronto. McLeod was already well-known in academia at that time, not only as an authority on glucose metabolism, but also with an advanced laboratory that met the requirements of Banting’s experiments. With enthusiasm and dedication, Banting was allowed to enter the laboratory of the academic world to carry out experiments.
  In May 1921, Banting and MacLeod’s 21-year-old student Best officially started the experimental journey of purifying insulin. The two young people divided the dogs used for the experiment into two groups. One group of experimental dogs received pancreatic duct ligation, and insulin was extracted from their bodies after the death of acinar cells. The other group of experimental dogs had their pancreas completely removed. During the experiment, the dogs in the second group had their pancreas removed and soon developed a typical diabetic symptom of elevated blood sugar. At this point, the substances extracted from the first group of experimental dogs were injected into the second group of dogs with pre-existing conditions to see if blood sugar levels would decrease.

  The experimental process seems simple, but for Banting and Best, who do not have proficient anatomical skills and are not familiar with endocrinology, biochemistry and other disciplines, the experiment was difficult at the beginning. Many dogs died of infections due to unsuccessful surgery during the removal of the pancreas and the ligation of the pancreatic ducts. That is to say, the experiment has not yet entered a substantive stage, and the experimental subjects have been seriously insufficient. In order to obtain enough subjects, the two young men racked their brains and went to great lengths. However, with the accumulation of experience and the improvement of their abilities, they finally obtained a relatively satisfactory pancreas after acinar cell death. The two men sliced ​​the pancreas, ground them into mince under freezing conditions, and immersed them in physiological saline to obtain a crude extract.

Banting (right) and Best

  Fate did not live up to their persistence, and after injecting their crude extract into a diabetic dog known as “Ninety-Two”, the dog was quickly rejuvenated. Before this experimental dog, at least 91 dogs had been “dedicated” to science under Banting’s scalpel. Macleod also quickly realized the importance of this successful experiment. He invited the biochemist Cripp to join the experiment, and the research group expanded to four people, who were later known as the “Toronto Four”. Subsequently, the research team improved the experimental method. Instead of waiting for the death of acinar cells to extract insulin through ligation, the crude pancreatic extract was directly extracted with ethanol. Cripp’s biochemical literacy helped the team further improve purity.
  In January 1922, the “Toronto Four” first used their extracted insulin on a child with diabetes, with immediate results, and continued success thereafter. Soon, the news spread far beyond the lab, and soon the spectacle at the beginning of this article appeared: a group of scrawny, dying people from different directions gathered in Toronto, waiting for an injection that would rejuvenate them. “Medicine.
  In 1923, Banting and MacLeod shared the Nobel Prize in Physiology or Medicine. At the age of 32, Banting was the youngest recipient of the Nobel Prize in physiology or medicine. It took only one year from the publication of the results to the award of the Nobel Prize, which shows the importance of the discovery of insulin and its application in the treatment of diabetes in the history of human development. Canada established the Banting-Best Institute for the first young man to win the Nobel Prize in its history, and appointed Banting as its first director. After Banting’s death in a plane crash in 1941, Best took over as director.
Achieving “agreement” in “disagreement”

  Banting and McLeod disagreed about who was more responsible for discovering and purifying insulin and who deserved the Nobel Prize. Banting believed that he and Best contributed more than Macleod, who gave half of his Nobel Prize to Best and Macleod to Cripp.
  The priority of scientific discovery is the “hard currency” of the scientific kingdom, and many scientists do not give in on this point. In many cases, this kind of debate is just for scientists to defend their supreme scientific honor, and there is no interest involved. Although the “Toronto quartet” is difficult to reach an agreement on “who has the greater contribution in discovering and saving insulin”, they have shown amazing agreement in saving diabetic patients and maintaining the health and safety of human life.
  At that time, the results in the laboratory of the “Toronto Four” saved many diabetic patients and brought back to life many patients who were struggling on the line of life and death. However, limited by the level of technology and craftsmanship, laboratory methods cannot extract insulin in large quantities, and most patients are still in a state of no medicine. This state stings the hearts of scientists and stimulates the enthusiasm of pharmaceutical companies for production. The “Toronto Four” jointly applied for a patent and transferred it to the University of Toronto at a very low price. In 1923, Eli Lilly, an American pharmaceutical company, obtained the right to use the patent, and was the first to improve the process to realize the mass production of insulin injection.



  Shortly after the success of Banting, MacLeod and others, Kroger, a Nobel laureate in physiology or medicine at the University of Copenhagen in Denmark, traveled with his wife to the United States. His wife, Mary, a doctor and diabetic, heard the story of the “Toronto Four” and sensed the great opportunity that lay in it. After the Krogers returned to Denmark, they incorporated Nordisk in 1923 and produced the first European insulin preparations to meet the needs of the European market.
  Since then, with the advancement of production technology, insulin production has continued to expand, and more and more diabetics have begun to truly benefit from the scientific achievements of the “Toronto Four”.
The battle against diabetes is not over

  While the turning battle of 1922 gave us a beautiful turnaround, the battle between humanity and diabetes is far from over.
  With the ability to extract insulin and apply it clinically, humans have only completed the first step in understanding insulin. As James Watson, one of the proponents of the double helix structure of DNA, put it in a 1964 paper: “It is impossible to accurately describe the function of a molecule at the chemical level unless we first know its structure.” In 1953 Before the publication of Watson and Crick’s paper “The Molecular Structure of Nucleic Acids,” mankind had not yet entered the era of molecular biology. Banting and McLeod as scientists and Eli Lilly and Nordisk as pharmaceutical companies all extract insulin from animals, but treat diseases in humans. Not only is the output limited, but it is difficult to avoid insulin resistance. At that time, how to achieve truly purified animal insulin was still a great problem.
  In 1955, after more than ten years of research, Sanger, a biochemist at the University of Cambridge in the United Kingdom, finally determined the sequence of the 51 amino acids that make up pig insulin, clarified the structure of this protein, and laid the foundation for the preparation of fully purified insulin. The foundation also provided the prerequisites for later gene pharmaceuticals. Sanger was awarded the Nobel Prize in Chemistry in 1958.
  In 1965, Chinese scientists synthesized artificial bovine insulin according to the amino acid sequence and structure of natural bovine insulin.
  In 1982, Genentech, an American genetic engineering technology company, used recombinant DNA technology to prepare human insulin with less rejection and faster effect, which greatly improved clinical safety.
  To this day, the story of humanity’s struggle with diabetes continues.
  Relevant statistics show that in 2019, the number of adults with diabetes in the world has reached 463 million (prevalence rate is 9.3%), and the number of adults with diabetes in the world is expected to increase to 578 million by 2030. Currently, diabetes is divided into type I and type II. Type I diabetes patients are mostly children; type II diabetes patients are mostly adults, and these patients often have common characteristics, such as obesity and lack of exercise. Type 1 diabetes is congenital, mainly because the body cannot produce insulin on its own. For such patients, supplementing insulin by injection can play a good role in controlling blood sugar, but multiple injections per day and life-long injections also bring certain difficulties to the patient’s life. Many people with type 2 diabetes have normal function of secreting insulin. If insulin resistance occurs, it means that the function of insulin to stimulate the body’s cells to absorb excess glucose or stop the production of glucose is impaired. This situation is far from being solved by insulin injection. No matter what type of diabetes is aimed at, with the goal of reducing the suffering of patients and improving the quality of life, scientists are still on the road of exploration.
  In the process of fighting against diabetes, although mankind has achieved unprecedented scientific achievements, saved countless lives by extracting and synthesizing insulin, and greatly improved the quality of life of patients, this battle has not yet come to a perfect end.