History of Insulin

17/01/2020

By:Elad Goren

From crude extracts to an accidental discovery of sulfa-like drugs in antibiotics, to the development of drugs based on our improved understanding of the pathophysiology of

diabetes mellitus.

The earliest description of diabetes is dating back to 552 BC, when it first appeared in a collection of medical texts in Egypt, the Ebers  Papyrus.(1,2)

Diabetes mellitus and it's remedies were also mentioned and described in ancient India and china.(1)

The term "Diabetes" is derived from the Greek word "Siphon" and was first introduced by Aretaeus of Cappadocia, a Greek physician, (129-199 AD).

He noted that diabetes causes constant flow of urine (2, 3)

Before the availability of insulin, the life expectancy of children with diabetes mellitus was short

and the prognosis for the adult onset diabetes was extremely poor

Before Insulin

Before the availability of insulin, during the first part of the 20th century, Frederick Allen and 

Elliott Joslin advocated severe fasting and calorie-restricted diets for diabetes (4).

All diabetics were advised to cut their sugar and dietary starch intake and patients who were obese were advised to lose weight.

These recommendations resulted in decreased coma rates, marginal improvement of acidosis

and glycosuria, and delayed death among diabetes children.

Insulin

The discovery of insulin in 1922 marked a significant breakthrough in medicine and therapy in patients with diabetes.

Prior to the discovery of insulin it was hypothesized that the pancreas secreted a substance that controlled carbohydrate metabolism (5).

For many years, pancreatic extract preparing attempts to lower blood glucose were unsuccessful

due to impurities and toxicities (6).

Frederic Banting who was an orthopedic surgeon came up with a brilliant idea of isolating pancreatic islet extracts by pancreatic duct of dogs, keeping them alive until the acini degenerated making the isolation possible.

He teamed up with John Macleod, who was a professor of physiology and department head at the University of Toronto, for some laboratory space.

Macleod decided to grant Banting: ten dogs for his In vivo experiments, laboratory space, a student research assistant as well as supervision and guidance.

His experiments began on May 17, 1921, and by September they showed depancreatized  dogs developed  diabetes  and   that intravenous injection with their  own pancreatic extract, (Iseltin),

lowered the blood glucose.

By the end of 1921, the biochemist J.B collip also joined the group.

He helped purifying the isletin for human use for the first time.

The very first injection of pancreatic extract to a patient was given to a 14-year-old boy by Banting and Best on January 11, 1992.

It caused a sterile abscess, resulted in mild blood glucose reduction and had no effect at all on

ketosis.

Subsequent injection of the purified extract yielded promising results that same year as blood glucose and glucosuria decreased and ketonuria disappeared.

Several months later all three scientists were jointly awarded the Nobel Prize.

Another breakthrough began when Eli Lilly developed an isoelectric precipitation method which led to much purer and more potent animal insulin.

The potency varied up to 25% per lot!

In 1923, August Krogh, from the University of Copenhagen, met with Banting and macleod to learn more about insulin because his was diagnoses with diabetes mellitus.

Krogh received authorization from the University of Toronto to bring insulin to Scandinavia, shortly thereafter, Nordisk Insulin Laboratory, today – the largest producer of Insulin in the world, began insulin production (6).

Insulin preparation required numerous injections daily, which is why investigators worked together to find ways to prolong its action of duration.

In the early 1930's,H.C. Hagedor, chemist in Denmark, managed to prolong  the action of insulin by simply adding  protamine to it (5).

In Toronto, Scott and Fisher managed to prolong insulin action even further by adding Zinc.

The addition of Zinc has made a big difference in the pharmacokinetic and effects of amorphous lente insulin (semilente, lente and ultralente) and has led to introduction of longer-acting animal insulins in the market such as protamine zinc insulin, which lasted 24-36 hours and neutral protamine Hagedorn which lasted almost 24 hours.

In 1978, the first RECOMBINANT DNA human insulin was prepared by David Geoddel by utilizing and combining insulin A and B - chains expressed in Escherichia coli.

Shortly after, both Lilly and Genentech signed an agreement to commercialize rDNA insulin.

In  1982, rapid insulin, Humulin^® R and NPH, intermediate - acting insulin, were marketed.

Both insulins incorporated the groundbreaking new rDNA technology.

Thanks to the aforementioned developments, the prognosis of patients with diabetes had improved and they started living longer.

Thus, chronic implications and complications of diabetes became very prevalent.

In 1993, the Diabetes Control and Complications Trail showed for the first time the linear relation between the degree of glycemic control and complications (8).

Physiological insulins that mimic basal and prandial insulin secretion were sought to reduce the incidence of hypoglycemia.

Modification of certain sites of amino acids in the insulin have led to changes in the pharmacokinetics which led  to a much faster absorption, earlier peak,  and shorter duration of action (9).

Lispro was the first short-acting insulin analog approved  in 1996 , followed  by aspart in 2000 (11) and glulisine in 2004 (12).

As for 2014 there were two basal insulin analogs in the market, glargine and detemir which was approved in 2005 (13).

Glargine has glycine instead of asparagine at position A21, two extra arginine molecules at position B30 and a pH of 4.0.

When being injected it forms microprecipitates at the site of injections which is resulting in prolonged absorption with little peak activity (14)

Insulin detemir has a 14-carbon fatty acid chain attached to lysine at position B29 which slows down its absorption.

Exubera, was the first alternative delivery method for insulin.

It was the first inhaled insulin which was developed by Sanofi-Aventis and Pfizer and marketed by Pfizer in 2006.

The inhaler device bulky and no easy to use and it did not add any benefits over rapid-short acting insulin analogs.(this article)

It was taken off the market after only 2 years when it failed to gain acceptance from patients and providers.

Pancreatic crude extracts gave hope to so many patients around the world with diabetes mellitus.

The development of more physiological precisely engineered insulin analogs also improved the control and helped delaying the complication of the disease.

Today Insulin remains the keystone of therapy along with other newer medications which oftentimes complement and even enhance insulin action. These medications are tailored toward other pathophysiological mechanisms of diabetes mellitus.

Refrences

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