The discovery of insulin

A Jahr100Wissen / 100 years ago interview with cell biologist Prof. Dr. Martin Simon from Wuppertal

First treated in 1921, the chronic metabolic disease diabetes mellitus, is known as diabetes. What happens in the body, when being diseased with diabetes?

Simon: First and foremost, it is a lack of insulin, or a lack of the effect of insulin. As a result, there is a misregulation of the sugar balance, the carbohydrate balance. This leads to cells wanting to burn sugar and needing the energy, but no longer getting it. A kind of feeling of weakness develops. At first, this is the primary effect. The long-term effects, however, are much more fatal. There is kidney damage, as more sugar is excreted through the kidneys in order to reduce the high blood sugar levels. And, of course, there is massive damage to the entire organism because the energy balance is upset.
As early as the 2nd century AD, diabetes is described in detail. It should be noted that, for centuries, people suffered extremely from it. The classic form of therapy was starvation, i.e. eating as little as possible and therefore no carbohydrates.The disease was not treatable. People who developed the symptoms and went into sugar shock from ingesting carbohydrates, could not be helped. Diabetes patients did not live very long. Insulin is our only hormone that can actually lower blood sugar levels. Several hormones can increase it, and they can even complement each other. When we have eaten food rich in carbohydrates, the pancreas releases insulin from the islets of Langerhans (islets of hormone-forming cells embedded in the pancreas). This then causes the cells, muscle tissue or liver that want to absorb sugar, to do so. Not all the sugar, which is distributed through the blood in the system or in the body, is automatically absorbed there. There must be a signal for the cell that says: now you should absorb sugar.

Frederick Banting, a Canadian surgeon, is considered to be the discoverer of the healing compound insulin. How did he find the substance?

Simon: Here, I have to clarify. He was not the first to actually isolate insulin. The Romanian Nicolae Paulescu had already isolated it from slaughterhouse waste in 1916 and also published it in 1921. But he made several mistakes. For example, he presented his results at a lecture in Romanian and the scientific paper he wrote was in French. At that time, however, the international community had already established itself for scientific exchange in English. And the results, as groundbreaking as they were, went completely unnoticed. Banting went with his first isolates and did not work on pigs at first, or cattle, but he did his experiments with dogs. He was also a trained surgeon, although not a very good one, because many of his dogs died of infections. Banting's approach was the following: He cut off the pancreas, which produces insulin, so that it no longer released the digestive juice and substances produced by the pancreas into the gastrointestinal tract, so to speak, but concentrated them.That was the surgical solution. After a few days, he then removed the pancreas, ground it up without much attempt at purification and then injected the homogenate intravenously into dogs suffering from diabetes. In this way, he was able to achieve a therapeutic effect in the dogs. He could therefore conclude that, at least, the substances he wanted were inside. The purifications of the insulin were then the other important steps that had to be taken before the medication could be produced. That is where Frederick Banting's Institute Director at the University of Toronto came in. Banting was able to enlist the institute's director John McLeod as an advocate, who liked his idea and gave it to him, even though he had no chemical/biochemical training other than surgery. McLoed provided Banting with both a laboratory and laboratory animals, as well as his assistant Charles Best.
Banting himself had already recognised that the preparation was also very unstable, i.e. the insulin was obviously degraded. He then separated trypsin-producing cells from the pancreas, which enabled him to stabilise the insulin.However, according to the literature, it was primarily McLeod who realised that he needed the help of a biochemist to obtain the insulin as a pure substance. This was also necessary in order to eventually move on to human patients, i.e. the substance had to be much purer in order to be tolerated.
However, the insulin we obtain as a pharmaceutical substance today is no longer isolated from slaughterhouse waste or from an animal system. Most of it is biotechnologically expressed in bacterial or yeast cells, i.e. the gene for the insulin is introduced into yeasts and then the precursor insulin is produced on an extremely large scale. At the time, Banting's experiments from the pig pancreas meant that a patient needed one pig pancreas per week of insulin. Today, that would no longer be feasible with the many type 2 diabetes cases that will statistically increase.Another advantage of biotechnological production is the modification of insulin. This means that individual amino acids can be exchanged, the behaviour of the insulin can be influenced and thus also its effectiveness. Both fast-acting and slow-acting insulins can be produced and then applied individually to the needs of a patient and his or her clinical picture. The production of insulin from bacteria is still not easy, as even today further chemical modifications have to be carried out after production. In mammals, the finished insulin is processed from a precursor protein. A part of the protein is removed, and the two marginal peptides are linked together by disulphide bridges. Bacteria do not have this enzymatic equipment, which is why these changes are realised by biochemical modifications to the precursor proteins.

Where does the name insulin come from anyway?

Simon: It actually comes from the term island, which is also in the name insulin. Not the entire pancreas produces insulin, but there are many different cell types in the pancreas. And there are the so-called islets of Langerhans, first described by the pathologist Paul Langerhans. In the microscope you can see them in histological section. These are collections of individual special cells. They are connected to the blood vessel system and are responsible for measuring the blood sugar level. They not only have the task of producing insulin, of secreting it, but also of measuring the blood sugar level as a regulatory function. And if it is too high, i.e. exceeds a threshold, then they produce insulin and release it into the bloodstream. This is where these islets of Langerhans are important. In cases of insulin deficiency, i.e. type 1 diabetes, even transplantation possibilities (islet transplantation) exist, if the islets of Langerhans are attacked due to autoimmune diseases.

The 5-year-old Ted Ryder was then one of the first patients to be treated with insulin in 1922. At the beginning of treatment, he weighed only 12 kilograms and died in 1993 at the age of 76. With 70 years of diabetes, he is probably the longest documented case of continuous insulin treatment in medical history. How many people actually have diabetes?

Simon: Of course, you have to distinguish between the different diabetes variants. We have diabetes type 1, which is an autoimmune disease, a relatively rare variant that about 10% of all diabetes patients have. The more common case is diabetes type 2, where the body still produces insulin, but the uptake into the recipient cells is disturbed or no longer takes place. Interestingly, here, the pancreas sometimes still produces more insulin because it tries to counter-regulate. This also works in the early stages of the disease.
Type 2 diabetes is what used to be called adult-onset diabetes. It only develops in the course of life and was often not diagnosed in time. Today, people are moving away from this term because new risk factors have been identified. These include, first and foremost, obesity. Because of obesity, many young people develop this type 2 diabetes. This accounts for 90% of diabetes cases.
In Germany, about 10% of the population suffers from diabetes. This is one of the major widespread diseases, although of course not all patients need to inject insulin. For the sake of completeness, gestational diabetes must also be included. In pregnancy, insulin function is blocked by hormones that are secreted by the placenta. The hormone system gets confused and there is a short-term form of diabetes that normally regulates itself again after delivery. Although, the risk of developing type 2 diabetes is seven times higher during pregnancy.If you add this up, you have an average prevalence of diabetes in Europe of 6.4%. It is really frightening that we also have an increased prevalence of type 1 diabetes of 3%. There is a new study by the DDZ (German Diabetes Centre) and the Robert Koch Institute, according to which the scientists forecast an increase of up to 77% in type 2 diabetes by 2040. The massive increase in the biggest risk factor, namely obesity, will have a severe impact in the near future. It is quite frightening to read that it now already affects almost 10% of the population in some countries. If you then add in such an increase, we are already at more than 15% of the population.  One must not forget that even type 2 diabetes patients have a shorter life expectancy, and despite the good treatment options, the disease still represents a severe impairment of the quality of life. Not to forget, of course, that it is a huge cost factor for our health system.

In 1923, Banting was the youngest physician to receive the Nobel Prize for Medicine, together with John McLeod. He received it for the discovery of insulin at the age of just 32. But the two were no longer friends after that. What had happened?

Simon: That is difficult to understand from the literature. Sometimes, it is described that they had been at loggerheads before. You can read that McLeod, as director of the institute, was very supportive of Banting. In the beginning, that worked well. McLeod later interfered meaningfully in the project, according to the lore, because he saw that Banting produced a relatively impure insulin. McLeod then arranged for a biochemist to join the team, who produced the insulin more purely in order to have the possibility of injecting an animal preparation into a human being.Now, the Nobel Prize went equally to the director of the Institute and the head of the AG. Charles Best, the assistant who made significant contributions, as well as the biochemist James Collin, who had done the purifications, went away empty-handed. Obviously, this interference caused a rift between the two. Banting split his prize money with Best. McLeod shared it with Collin. It is difficult to judge what real contribution McLeod made to the project. And you cannot ask her today.

Uwe Blass (Interview on August 16, 2021)

Martin Simon studied at TU Kaiserslautern until 2005. He then became an assistant professor at Saarland University in 2012. Since 2018, he has been head of the Molecular Cell Biology and Microbiology department in the Faculty of Mathematics and Natural Sciences at the University of Wuppertal.