The Development of Insulin

In order to better understand the world we live in, we must look to where we have been. This 3-part Diabetes Past & Present series will examine different elements of diabetes in history and discuss how these stories relate to current events in the community. We’ll start by looking at the history of insulin.

I wish I could say that when my pancreas quit on me all those years ago, I said ‘thank you, next’ and decided I was better off without it. Insulin? Who needs her? Wait–I do. And it isn’t just me with the co-dependency problem! We all do. 

That precious clear liquid is a literal lifeline for people with diabetes. Thanks to a team of Toronto scientists—Frederick Banting, Charles Best, John Macleod, and James Collip—discovering insulin in 1921, folks diagnosed with diabetes could begin to survive and thrive. So, after almost 100 years, what has changed about insulin manufacturing, and what types of insulin are available now? In the first instalment of this series, I will tell the story of this landmark medical discovery and use it as context to discuss more recent developments in insulin.

First, I need to set the stage about what it was like to have diabetes before insulin was discovered. Bear with me, this was a bad time for people with diabetes. If we’re going all the way back, the first recorded mention of diabetes that we know about was in an Egyptian manuscript from 1500 BC [1]!

Diabetes was initially characterized as “too great emptying of urine” that tasted “sweet like honey” [2]. How did they know what the urine tasted like, you ask? Well, Indian physicians knew it attracted ants and a London physician named Thomas Willis deserves a major shoutout for drinking his patients’ pee to diagnose them [3]. Willis was also known to refer to diabetes as “the pissing evil”. 

At this point, a diagnosis with diabetes was basically a death sentence. Without insulin around, doctors prescribed some interesting treatments to try and prolong their patient’s lives (jelly of viper’s flesh, anyone?) [4]. Harsh diets with limited calories and carbohydrates became common and sometimes patients died of starvation [5].

While Banting and Best usually get all the credit for discovering insulin, there were a few people before them that made it possible. Paul Langerhans identified pancreatic islets in 1869, and von Mering and Minkowski found that the removal of the pancreas led to diabetes in dogs in 1889. (Warning to fellow dog lovers! A lot of initial insulin research, unfortunately, involved dogs as test subjects). Two scientists named de Mayer and Schaefer both identified islet cell secretions in 1909 and 1910 respectively [6]. Prior to Banting, a few scientists including a Romanian group had already produced pancreatic extracts that lowered blood sugar levels in animals, however, these extracts were accompanied by toxic side effects and the research didn’t move forward as quickly [7]. 

After centuries of doom and gloom, the twenties is really when the tide started to turn for people with diabetes. In the fall of 1920, Frederick Banting was working as a surgeon in London, ON, and teaching classes. When preparing to teach a lecture about the pancreas, he read a journal article entitled “The Relation of Islets of Langerhans to Diabetes” by Moses Barron of the University of Minnesota, sparking an idea for how to extract islet cell secretions while protecting it from destruction by other pancreatic enzymes [8].

He brought his idea to J.J.R. Macleod, the head of physiology at the University of Toronto. Banting had little experience or knowledge of the field, but Macleod reluctantly agreed to give him space in his lab. Macleod also granted him the help of a senior undergraduate student research assistant, Charles Best. Best was there to help with all the chemical testing—he knew how to measure blood sugar and urine sugar levels [9].

Over the course of essentially one summer, Banting and Best, under the supervision of Macleod, developed a system for extracting islet cell secretions from dogs and administering it to pancreas-less dogs to lower their BG levels. Because it was difficult to obtain large amounts of such extract, they soon developed a new protocol for isolating whole pancreas extracts from cows [10].

Manufacturing insulin at a large scale proved to be difficult. The Toronto team received an American patent on insulin and Toronto’s preparation method in 1923 for quality assurance [15]. Banting, Collip, and Best sold the patents to the University of Toronto for $1.00 each. Cue Banting’s famous words: “insulin belongs to the world, not to me” [16]. 

The University of Toronto also accepted an offer of collaboration from Eli Lilly and Co., an American pharmaceutical company, to aid in the manufacturing of insulin [17]. August Krogh, who was married to a woman with diabetes, visited Toronto from the University of Copenhagen and was authorized to make insulin in Scandinavia, founding Nordisk Insulin Laboratory [18]. Connaught Laboratories at the University of Toronto were responsible for making insulin in Canada. Connaught Labs expanded over the years and continued making insulin through the seventies. Through a series of acquisitions, what used to be Connaught has become a part of Sanofi [19]. The “Big Three”, Eli Lilly and Co., NovoNordisk, and Sanofi continue to control most of the world’s insulin market.

Soon after in 1955, Novo Laboratories in Denmark introduced the Lente Insulin line which was also combined with zinc. One variation, Semilente, was soluble in blood and fast-acting, while Ultralente was insoluble in blood and slow-acting [21].    

Up until this point, insulin was still derived from animal pancreases. This meant that a) insulin manufacturing was dependent on supply from the meatpacking industry and b) injected insulin caused some patients to have adverse immune reactions [22]. Alleviating both these problems, the first synthetic human insulin was produced in 1978. A groundbreaking moment for the biotech industry, scientists at Genentech used recombinant DNA technology to express the insulin gene in E. coli [23]. In this way, insulin could be made by bacteria instead of being extracted from animals. Eli Lilly released the first synthetic human insulin under the name “Humulin” in 1982. Vegans with diabetes, rejoice!

In 1996, Eli Lilly marketed the first analogue insulin, “Humalog” [24]. Analogue insulins are genetically modified to change how they are metabolized by the body. Other examples include NovoRapid and Lantus. There has also been growing interest in bringing more “biosimilar” insulins to market as patents expire, ideally serving as lower-cost alternatives to existing insulin products. Despite being around for so long, insulin is still unaffordable for many people living with diabetes. Introducing competition from biosimilar versions of insulin may be a way to increase accessibility.

A lot has happened in the world of insulin since the summer of 1921! As folks with diabetes, we are often looking forward to the next big thing—pumps, CGMs, bionic pancreases? islet cell transplants?! But, it is also nice to look back every once in a while. So, next time you pull out your insulin to change your infusion set or give an injection, I challenge you to remember the rich history behind it.