17 June 2021

The story of insulin – Part 2: A century of progress.

Since the invention of insulin treatment in 1921, researchers have continued to make significant advancements to this life-saving therapy.

The race to commercialize insulin began soon after Leonard Thompson’s life was saved by the world’s first insulin injection (click to read Part 1 – Saving a boy’s life).

Frederick Banting.

During the spring of 1922, Frederick Banting’s laboratory partner Charles Best was working hard on improving insulin treatment. He was now able to extract much more of the hormone from a bovine pancreas, but it was still not pure enough for wider medical use. At this point Banting and Best decided to take up an offer from a pharmaceutical company that remains strong in diabetes treatment today: Eli Lilly.

It was the company’s head chemist, George B. Walden, who made the scientific discovery that would be instrumental in producing refined insulin in large quantities. Walden’s discovery was isoelectric precipitation, a pH process that reduces the primary charge of a protein to zero.

Eli Lilly began selling insulin in 1923. That same year, the University of Toronto researchers who had discovered and first developed insulin treatment took home the Nobel Prize in Physiology or Medicine.

“Short-acting bolus insulins allow greater control of blood glucose around mealtimes, as appropriate doses can be administered to assist carbohydrate conversion in the hours immediately after eating.”

The road to NPH insulin.

For the next several decades, scientists would continue to make advances around purifying animal-sourced insulin and understanding its molecules. In late 1925, US biochemist and pharmacologist John Jacob Abel crystalized insulin for the first time, and in 1935 its amino acids were isolated by researchers Hans Jensen and Earl A. Evans Jr.

Another big breakthrough in the 1930s would come from Danish scientist Hans Christian Hagedorn, the founder of Nordisk Insulinlaboratorium – now known as Novo Nordisk.

Hagedorn was interested in slowing down the rate at which insulin was absorbed into the bloodstream, as this would mean people with diabetes could reduce their number of injections. He knew that proteins slowed absorption down, but they could often have contaminating side effects.

In searching for a better protein, Hagedorn would isolate protamine from fish – specifically river trout – to find out that it caused insulin molecules to come together in clumps that took longer to dissolve. He had discovered what came to be known as NPH (Neutral Protamine Hagedorn) insulin – one of the world’s earliest examples of engineered drug delivery. Novo Nordisk began selling NPH insulin in the 1950s.

Insulin crystals.

Synthetic insulin opens new doors.

for the first time. This important step would eliminate the need for animal insulin as the starting point for human insulin production. US geneticist Arthur Riggs and Japanese organic chemist Keiichi Itakura first produced artificial insulin in 1978 in collaboration with American biotech pioneer Genentech. Some three years later, Genentech began selling the world’s first biosynthetic human insulin: Humulin.

Today, the vast majority of insulins used worldwide are of the biosynthetic kind. These are often called human insulins, in that they are created in a lab to mimic the insulin produced in the human pancreas. During the 1990s, researchers began improving the characteristics of human insulins by modifying certain amino acids in the chain of insulin molecules. By doing so, they created so-called insulin analogs, with the word ‘analog’ representing how these insulins are ‘analogous’ to other human insulins. Insulin analogs are designed to provide an improved pharmacokinetic (PK) and pharmacodynamic (PD) profile compared to traditional human insulin.

Long-acting basal insulin analogs can reduce the number of injections needed. They also offer a smoother blood-glucose profile with potentially fewer dangerous episodes of hypoglycemia (a deficiency of glucose in the bloodstream). Short-acting bolus insulin analogs allow greater control of blood glucose around mealtimes, as appropriate doses can be administered to assist carbohydrate conversion in the minutes immediately after eating.

“Today, hundreds of millions of people around the world use insulin – often daily – to keep their diabetes under control.”

What comes next for insulin?

It’s now almost 100 years since Leonard Thompson received the world’s first life-saving insulin injection. Today, millions of people around the world use insulin daily to keep their diabetes under control. They are able to do so thanks to the decades of R&D that has been invested in improving the quality, availability and administration of insulin.

For the next generation of insulins, R&D is focused on two promising areas: glucose-responsive insulin, and insulin that can be consumed orally. While it’s still early days for glucose-responsive insulin – also called ‘smart insulin’ – the aim is to create an insulin that would fluctuate it’s activity depending on blood-glucose levels. This would make managing diabetes significantly easier. Oral consumption of insulin through pills is also aimed at making diabetes treatment more convenient. Oral solutions hold promise for eliminating the discomfort and inconvenience of current insulin-delivery methods that involve puncturing the skin.

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