The Discovery of Insulin: How a Peptide Changed the World

Insulin & Analogs

100+ years of insulin therapy

Insulin was the first peptide drug ever used in humans. Since its discovery in 1921, it has become the basis for four Nobel Prizes and over 100 approved peptide therapeutics.

d'Aloisio et al., Drug Discovery Today, 2021

d'Aloisio et al., Drug Discovery Today, 2021

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Before 1922, a diagnosis of type 1 diabetes was a death sentence. Children wasted away over weeks to months. The only treatment was a starvation diet that extended life briefly at the cost of constant misery. Then, in January 1922, a 14-year-old boy named Leonard Thompson received an injection of a crude pancreatic extract at Toronto General Hospital, and his blood sugar dropped. Within months, children across North America were being pulled back from the edge of death by a peptide hormone that nobody had been able to isolate until a young surgeon and a medical student spent the summer of 1921 in a borrowed laboratory. Insulin was the first peptide drug ever used in a human. As of 2020, over 100 peptide therapeutics and diagnostics had been approved worldwide, but insulin remains the most prescribed and the most consequential.^[1] For a complete overview of today's insulin biosimilars and how modern formulations compare, see the cluster pillar.

Before Insulin: What Diabetes Meant

Type 1 diabetes was recognized as a wasting disease for thousands of years. The ancient Egyptians described it around 1500 BCE. By the early 1900s, physicians understood that the pancreas was involved and that removing it from dogs produced diabetes-like symptoms. But isolating the active substance from the pancreas proved maddeningly difficult: digestive enzymes in the organ destroyed the hormone before it could be extracted.

The state of the art before 1921 was Frederick Allen's starvation therapy. Patients were put on diets of 400-500 calories per day. This slowed the progression of hyperglycemia but left patients skeletal and miserable. Children admitted to diabetes wards looked like famine victims. Most died within one to two years of diagnosis.

The Summer of 1921: Banting, Best, and a Borrowed Lab

Frederick Banting was a 29-year-old orthopedic surgeon in London, Ontario, with a failing private practice and no research experience. On October 31, 1920, he read an article describing how ligation of the pancreatic duct caused the digestive-enzyme-producing cells to degenerate while leaving the islets of Langerhans intact. He wrote a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these to relieve glycosuria."

On November 7, 1920, Banting brought his idea to J.J.R. Macleod, a respected diabetes researcher and professor of physiology at the University of Toronto. Macleod was skeptical but offered Banting lab space, 10 dogs, and a medical student assistant named Charles Best.

Banting and Best began work on May 17, 1921. By July 27, they had prepared a pancreatic extract from a duct-ligated dog and injected it into a diabetic dog whose pancreas had been removed. The dog's blood sugar dropped from 200 mg/dL to 120 mg/dL within an hour. They named the extract "isletin."

Over the following months, the results were replicated across multiple dogs. James Collip, a biochemist, joined the team and developed purification methods that made the extract safe enough for human use. The active substance was renamed "insulin," from the Latin insula (island), referring to the islets of Langerhans.

Leonard Thompson: The First Human Injection

On January 11, 1922, Leonard Thompson, a 14-year-old boy weighing just 65 pounds, received the first therapeutic insulin injection at Toronto General Hospital. The initial preparation was impure and caused an allergic abscess at the injection site. Twelve days later, on January 23, Thompson received a second injection using Collip's improved extract. His blood sugar dropped from 520 mg/dL to 120 mg/dL. Ketone bodies in his urine disappeared. He gained weight. He went on to live for 13 more years, dying in 1935 at age 27 from pneumonia.

The speed of insulin's clinical adoption was remarkable by any era's standards. By the spring of 1922, six more patients were being treated in Toronto. Eli Lilly and Company began mass production in late 1922, and by October 1923, commercial insulin was shipping across North America.

Banting and Macleod received the 1923 Nobel Prize in Physiology or Medicine. The decision was controversial: Banting felt Best had been overlooked and shared his prize money with him, while Macleod shared his with Collip. The dispute over credit has never been fully resolved.

Four Nobel Prizes: Insulin's Scientific Legacy

Insulin's impact extends far beyond diabetes treatment. Research on this one peptide hormone produced four Nobel Prizes across four decades:

1923: Discovery (Banting and Macleod). The first therapeutic use of a peptide hormone in humans.

1958: Amino acid sequencing (Frederick Sanger). Sanger spent a decade determining the complete amino acid sequence of insulin, published in 1955. This was the first time anyone had determined the full chemical structure of a protein. Insulin is 51 amino acids arranged in two chains (A-chain: 21 amino acids; B-chain: 30 amino acids) connected by two disulfide bridges. Sanger's work proved that proteins are not random polymers but have precise, genetically determined sequences. This finding was foundational for all of molecular biology.

1964: X-ray crystallography (Dorothy Hodgkin). Hodgkin determined the three-dimensional structure of insulin using X-ray crystallography, work that began in 1934 but was not completed until 1969 (her Nobel recognized earlier crystallography work, though insulin was her most ambitious project). Understanding insulin's 3D shape later enabled the rational design of insulin analogs.

1977: Radioimmunoassay (Rosalyn Yalow). Yalow and Solomon Berson developed the radioimmunoassay (RIA) using insulin as the model peptide. RIA made it possible to measure tiny amounts of hormones in blood for the first time, revolutionizing endocrinology and clinical diagnostics. C-peptide, the fragment cleaved from proinsulin during insulin production, became a key diabetes biomarker measured by techniques descended from Yalow's work.^[4] For more on how C-peptide functions as a diabetes marker, see the dedicated article.

From Pig Pancreas to Recombinant DNA

For 60 years after its discovery, all insulin came from animal sources, primarily pigs and cattle. Porcine insulin differs from human insulin by a single amino acid; bovine insulin differs by three. Both work in humans, but some patients developed antibodies that reduced efficacy or caused allergic reactions.

The solution came from genetic engineering. In 1978, researchers at Genentech synthesized genes encoding the A and B chains of human insulin and inserted them into E. coli bacteria. The bacteria produced authentic human insulin protein. In 1982, Eli Lilly's Humulin became the first genetically engineered pharmaceutical product approved by the FDA.

Recombinant DNA technology did not just solve the supply and immunogenicity problems. It opened the door to rational modification of the insulin molecule, which led directly to the modern analog revolution.

The Analog Revolution: Engineering Better Insulins

Once researchers could produce insulin in bacteria, they could alter its amino acid sequence to change its pharmacokinetic properties. This produced two major categories of insulin analogs:

Rapid-acting analogs are engineered to dissociate from hexamers faster than native insulin, reaching peak action within 15-30 minutes instead of 60-90 minutes. Insulin lispro (Humalog, 1996) was the first, created by swapping two amino acids at positions B28 and B29. Insulin aspart (NovoRapid, 2000) and insulin glulisine (Apidra, 2004) followed with different single-residue changes. For a detailed comparison of rapid-acting and long-acting insulin analogs, see the dedicated analysis.

Long-acting basal analogs are modified to form slow-release depots after injection or to bind albumin in the blood, extending their duration to 24 hours or more. Insulin glargine (Lantus, 2000) changed two amino acids to shift the isoelectric point, causing the molecule to precipitate at physiological pH and dissolve slowly. Insulin detemir (Levemir, 2004) added a fatty acid chain that binds serum albumin. Insulin degludec (Tresiba, 2012) forms multi-hexamer chains that release monomers slowly over more than 42 hours.

Each of these analogs is a lesson in peptide engineering: a single amino acid substitution or chemical modification can fundamentally alter absorption, duration, and clinical utility.

The next frontier is oral insulin delivery, which has been a goal since the 1920s. Recent work using cyclic peptide-based carrier technologies has demonstrated efficient oral delivery of zinc-stabilized insulin hexamers in diabetic mice, with glycemic efficacy comparable to injected insulin.^[3] For an overview of what's coming in smart insulin, oral delivery, and beyond, see the frontier article.

What Insulin Taught the Peptide Field

Insulin's journey from discovery to global pharmaceutical product established the template for peptide drug development. Several principles emerged:

Peptides can be drugs. Before insulin, the idea of a naturally occurring peptide as a pharmaceutical was unproven. Insulin demonstrated that a short protein with a defined sequence could be manufactured, standardized, and administered to millions. As of 2020, the PepTherDia database catalogued over 100 approved peptide therapeutics and diagnostics, spanning 26 therapeutic areas.^[1]

Delivery matters as much as the molecule. Insulin cannot survive the digestive tract (a challenge shared by nearly all peptide drugs). The field's ongoing struggle with peptide delivery traces back to the earliest insulin formulations. Solutions developed for insulin, including subcutaneous injection, slow-release depot formulations, and pen devices, became standard across the peptide drug class.

Peptide engineering works. The analog revolution showed that modest changes to a peptide's amino acid sequence or chemical modification can create clinically meaningful differences in pharmacokinetics. This principle now drives the design of GLP-1 receptor agonists (semaglutide's fatty acid acylation extends its half-life from minutes to a week), growth hormone secretagogues, and dozens of other peptide drugs.

Proinsulin processing reveals peptide biology. The discovery that insulin is synthesized as a larger precursor (preproinsulin), processed through proinsulin, and cleaved to release the active A and B chains plus C-peptide established the prohormone concept. This processing pathway is now known to apply to dozens of peptide hormones. Recent research has shown that proinsulin processing efficiency improves during GLP-1 receptor agonist treatment, mediated by weight loss rather than direct drug effects on beta cells.^[5]

Peptide immunotherapy is possible. Research using proinsulin-derived peptides has explored whether targeted immune modulation can slow the autoimmune destruction that causes type 1 diabetes. A 2017 trial in 27 newly diagnosed patients found that intradermal injections of proinsulin peptide preserved C-peptide levels (a marker of remaining beta cell function) with no systemic immune suppression.^[2]

For a broader map of how insulin fits into the network of peptide hormones that control glucose, including GLP-1, glucagon, amylin, and GIP, see the complete guide. The role of pramlintide as an insulin complement shows how another pancreatic peptide fills gaps that insulin alone cannot.

The Bottom Line

Insulin's discovery in 1921 transformed type 1 diabetes from a death sentence into a manageable condition, but its impact extends far beyond one disease. As the first peptide drug, insulin established that naturally occurring peptide hormones could be manufactured, modified, and used as pharmaceuticals. The scientific research it catalyzed produced four Nobel Prizes and laid the groundwork for the entire modern peptide therapeutics industry, now encompassing over 100 approved drugs. Every peptide drug on the market today exists, in some sense, because insulin proved the concept first.

Frequently Asked Questions

Who discovered insulin and when?

Frederick Banting and Charles Best isolated the active pancreatic extract at the University of Toronto in the summer of 1921, with key contributions from biochemist James Collip and lab director J.J.R. Macleod. The first therapeutic use in a human was on January 11, 1922, when 14-year-old Leonard Thompson received an injection at Toronto General Hospital. Banting and Macleod received the 1923 Nobel Prize.

Is insulin a peptide or a protein?

Insulin is classified as a peptide hormone. It consists of 51 amino acids arranged in two chains (A-chain: 21 amino acids, B-chain: 30 amino acids) connected by two disulfide bridges. The conventional boundary between "peptide" and "protein" is typically around 50-100 amino acids. At 51 residues, insulin sits right at the border, but it is universally categorized as a peptide hormone in endocrinology and pharmacology.

How many Nobel Prizes are connected to insulin?

Four Nobel Prizes have direct connections to insulin research: the 1923 Prize for its discovery (Banting and Macleod), the 1958 Prize for sequencing its amino acid structure (Sanger), the 1964 Prize for X-ray crystallography that included work on insulin's 3D structure (Hodgkin), and the 1977 Prize for developing the radioimmunoassay using insulin as the model peptide (Yalow).

When was synthetic insulin first made?

Recombinant human insulin (Humulin) was approved by the FDA in 1982, becoming the first genetically engineered pharmaceutical product. Scientists at Genentech cloned human insulin genes into E. coli bacteria in 1978. Before recombinant insulin, all insulin came from pig and cow pancreases, which occasionally caused immune reactions due to slight amino acid differences.

How has insulin changed since it was discovered?

Insulin has evolved from crude animal pancreas extracts (1922) to purified animal insulin (1930s-1970s), recombinant human insulin (1982), rapid-acting analogs like lispro (1996), and ultra-long-acting analogs like degludec (2012). Each generation modified the 51-amino-acid sequence or added chemical modifications to improve timing, reduce immune reactions, or extend duration. Current research pursues oral delivery and glucose-responsive "smart" insulins.^[3]

Why is insulin important for the peptide drug field?

Insulin was the first peptide used as a drug in humans, proving that naturally occurring peptide hormones could be manufactured, standardized, and prescribed at scale. As of 2020, over 100 peptide therapeutics were approved globally across 26 therapeutic areas.^[1] Techniques developed for insulin, including recombinant DNA production, amino acid engineering, and subcutaneous delivery, became the foundation for the entire peptide drug industry.