The History and Consequences of Discovering Insulin

April 17, 2019

It's been nearly a century since one of the greatest medical findings reached patients. How has the story of insulin changed modern diabetes care?

There’s an estimated 30 million Americans with diabetes. Another 86 million have prediabetes, of whom 30% will develop diabetes over a five-year period. It is the fastest growing chronic disease in the US. For the 6% and growing patient population with type 1 diabetes (T1D), insulin is necessary for survival.

It’s not an exaggeration to call insulin a life-saving drug. Since its discovery in 1923, millions of people have enjoyed longer lives than projected, and reduced complications due to their disease. Patients with T1D were previously “treated” with borderline-starvation diets and given life expectancies of just a few years.

The basis of the diet regimen—popularized in the decade leading up to the discovery of insulin—was to completely limit calories for a period of time, leading to dramatic loss of weight before reintroducing the patient to a high-fat, high-protein diet with no carbohydrates. In writing on the strategy, prominent physician Eliot Proctor Joslin, MD, noted that patients were starved with only the “faint hope that something new would appear.”

Enter insulin, in 1923.

It had been known for a half-century that blood sugar was central to the problem of diabetes. The importance of the pancreas in carbohydrate metabolism was known since 1880, when German physicians Joseph von Mering and Oskar Minkowski successfully removed the pancreas of a dog and showed that it led to a syndrome of high blood sugar, glucosuria, and eventual death.

Before then, in 1869, investigators discovered 2 types of cells in the pancreas—acinar cells are responsible for the digestive functions, and the islets of Langerhans secreted sugar.

Near the same era, Romanian scientist Nicolae Paulescu was experimenting with an aqueous pancreatic extract which reduced blood sugar when injected into diabetic dogs. He called this substance pancreine. When World War 1 broke out, he stopped his experiments for several years. He actually patented his product in 1922 with the Romanian patent office, but he never was officially credited with the discovery of insulin—because at the same time, 2 Canadian researchers, Sir Frederick Grant Banting, and John Macleod, published a paper on the successful use of an alcohol-based pancreatic extract for normalizing blood sugar in a human being.

In addition to helping develop insulin, Palescu was also aware there were other enzymes in the pancreas which played a role in regulating blood sugar—something not investigated for the next 50 years, and today play an important role in the treatment of diabetes.

Banting’s work began with his discovery that by ligating the pancreatic duct on dogs, and then removing the pancreas intact, he could isolate insulin without it being destroyed by the digestive pancreatic enzymes. He was able to isolate a small amount of a pancreatic enzyme— which he injected into a diabetic dog, demonstrating a drop in glucose.

The process was repeated several times, but was tedious and the yields small. This procedure was only able to harvest a small amount of insulin and was time-consuming, so they decided to use cattle as a source of pancreatic enzymes.

The next step came about trying to purify it and testing it on rabbits. The work was done under the supervision of McCleod. Once a good process of purification of insulin occurred, the first human trial occurred in 1922 with the injection of insulin into a 14 year-old boy. Miraculously, it dropped his blood sugar into a normal range, and he didn’t die. Several more human trials were developed, which clearly showed that extract could reduce blood sugar in humans.

Banting, and McCleod were given the Nobel Prize in Medicine in 1923 for their work in discovering insulin. It created a controversy that endures to this day as to who should have really earned recognition for the discovery. Ultimately, it was Banting who was given the commercial rights to insulin, which he donated to the University of Toronto for $1.

Producing insulin commercially was a huge undertaking. Banting sought help from company Eli Lilly to help produce insulin which was now being extracted from rabbits, granting them a non-exclusive licensing right to develop insulin. The non-exclusivity allowed other companies to also work with insulin.

Initially, there were major problems with the reliability of the insulin extracts, and the extracts deteriorated quickly, and lacked consistency from batch to batch. The problem was solved by discovery that insulin must be prepared at a specific PH which would ensure purity and quality control. The so-called “isoelectric precipitation” method allowed Eli Lily to produce insulin in large quantities—although there remained problems with standardization. The University of Toronto was able to maintain control of insulin, but licensed it to several companies to develop.

Banting stated repeatedly that he did not want any company to have complete control, so as to allow insulin to remain available cheaply for patients in need. Over time, new proportions of insulin were developed to increase or decrease the duration of effect.

In 1936 Hans Hagedorn and August Krogh obtained the rights to insulin from the University of Toronto. They formed the company Nordisk Insulin Laboratorium. They discovered that insulin could be prolonged by adding protamine obtained from the semen of river trout. Protamine zinc insulin lasted 24-36 hours, making it somewhat unmanageable due to prolonged hypoglycemia.

One problem with all insulins produced up to 1982 was that it was derived from animal sources and could produce allergic reactions, and reactions at the injection sites. It sometimes produced inconsistent results as well.

A major breakthrough occurred in 1978, when Genentech was able to synthesize the first human insulin molecule. Once the genetic code was known, scientists at Lilly were able to insert the DNA sequence into E. coli and harvest human insulin in large quantities. Human insulin was patentable, and was released in 1982 on the market in 2 forms: a regular or short-acting form or intermediate-acting form. These products were not likely to produce allergic reactions and were very consistent in their effects. What was lacking, however was the ability of these insulins to act like insulin when secreted by the pancreas in normal subjects, because the onset of action couldn’t be matched.

Over the years scientists, altered the amino acid sequences of the human insulin to more closely mimic the effect of in vivo insulin. They created products that were quicker-onset and longer lasting. They also developed novel delivery systems like insulin pens, and pumps to make administration and storage of insulin convenient and painless.

As I said, T1D insulin is a life saver. For many patients with type 2 diabetes, insulin can be added to other therapies to control glucose and reduce complications. The discovery of insulin was a tremendous scientific breakthrough, but like many great things, there are negative unintended consequences.

Insulin prolongs the life of patients long enough for them to get worse complications of their disease including blindness, renal failure, and cardiovascular disease prematurely. There remains no way of reducing the risk of passing along genetic predisposition to patients’ children. Lastly, it can be argued that the discovery of insulin stopped further research into diabetes, neglecting some important hormones that play key roles in glucose metabolism.

It’s only been in the last 20 years that we have recognized and developed drugs besides insulin to treat type 2 diabetes. These products have changed the lives of people with T2D, and offer the chance to avoid the complications of insulin therapy. It has been said—albeit tongue-in-cheek—that the discovery of insulin was the worst thing that has ever happened to type 2 diabetes.

But it can’t be denied that insulin has saved millions of lives in T1D care, and was arguably the greatest medical miracle of this century. As with everything in life, nothing is black and white, and all good things carry some unintended consequences.