The History of Insulin Therapy1

The chronicle of diabetes symptoms as described by Galen and Arateus (Greek physicians) is worth mentioning. They gave a lucid portrayal of 2diabetes as “relentless flow of urine, insatiable thirst leading to wasting of flesh and limbs into the urine followed by a very speedy death.” Arateus coined the term “Diabetes” which in Greek means “siphon”. John Rollo, a surgeon was the first to add adjective “Mellitus” which means honey.

In 1674, Thomas Willis, a professor of natural philosophy at Oxford, brought into notice the fact that urine of patients with diabetes was sweet but he could not isolate the sweet chemical in the urine. About a century later, in 1776, Mathew Dobson of England isolated and identified the sweet substance in urine as “brown sugar”.

Cawley in 1788 reported a case with shriveled pancreas with stones. Till the middle of the 19th century, many other physicians observed postmortem findings of diseased, atrophic, or calculus pancreas. But contradictory to that, pancreas of many patients were absolutely normal at autopsy. This negated the view that pancreas could be the causative organ. Negative role of pancreas in causation of diabetes was further strengthened by separate experiments in dogs by Claude Bernard and Moritz Schiff between 1840s and 1860s. Their experiments involved ligation of pancreatic ducts and injecting them with oil or paraffin to block all duct secretions which led to near total atrophy of pancreas. But the dogs did not show any symptoms or signs suggestive of diabetes. It was to be discovered later that pancreas not secrete only the digestive enzymes but was also a gland of internal secretion.

It was Bouchardat, whose published work in 1875 suggested pancreas to be the organ responsible for diabetes. Two years later, Lancrereaux in 1877 published similar results and described at least two different types of diabetes:

As diabetes gras was much more prevalent than the diabetes maigre, it became clearer that why postmortem findings of pancreatic lesions were most of the times negative.

In 1889, Joseph von Mering and Oscar Minkowski performed experiments on dogs which proved that pancreas is a gland of internal secretion. They did total pancreatectomy in dogs subsequent to which dogs developed polyuria within few hours and the urine tested positive for glucose. Mering and Minkowski implanted a small portion of pancreatic gland in the subcutaneous tissue of the depancreatized dogs which corrected the glucosuria and the symptoms of diabetes. This was a historical ascertainment which ultimately led to establishment of pancreas as the causative organ for diabetes.

A German medical student, Paul Langerhans in 1869 described heaps of cells different from pancreatic acinar cells but did not hypothesize their function. Laguesse in 1893 named these heaps of cells as “Islets of Langerhans” and suggested them to be the gland of internal secretion of pancreas. The description of hyalinization of islets in patients with diabetes by American pathologist Eugene Opie in 1900s linked islets to diabetes.

Even after it was clear that the glucose lowering molecule was secreted from the islets, its exact nature was still elusive. John de Meyer was the first to coin the term “Insulin” (Latin: insula, island) in 1909 for the glucose lowering pancreatic islet secretion which was still not isolated.

For almost 35 years, many researchers prepared pancreatic extracts that were often successful in lowering BG in test animals. However, inability to remove impurities and presence of toxic reactions like fever, infections, and hypoglycemia prevented its use in diabetics.

An article written by Moses Barron in 1920s describing a case of pancreatic stone that blocked the main pancreatic duct stimulated Banting's research interests. The case described degeneration of acinar glandular cells secondary to the stone but not the islet cells.

Banting attributed earlier failures in isolation of the active principle to digestive enzyme “Trypsin” secreted by pancreas. He hypothesized that ligation of pancreatic ducts before extraction of pancreatic extract destroys trypsin secreting part though islets remained intact.

Banting was provided by Macleod a laboratory space, a student assistant, Charles Best, and an allotment of dogs to test his hypothesis. Applying Banting's hypothesis into practice, Banting and Best with the help of Macleod succeeded in isolating an extract of pancreas that reduced the signs and symptoms of hyperglycemia in depancreatomized dogs.

They next developed a procedure for extraction from the entire pancreas without prior duct ligation. This extract prepared from beef pancreas was successful for treating humans. Purification of the extract was mainly a work of Collip. In cooperation with Eli Lilly and company, the yield and standardization were improved.

In 1922, Leonard Thompson, a 14 years old suffering from type 1 diabetes, was the first patient who received the crude pancreatic extract developed by Banting et al. Following the first injection, the hyperglycemia reduced slightly but the symptoms did not go. But over next 3 weeks with repeated injections, he became euglycemic and came out of metabolic acidosis.

A few months later, Banting and his team started facing difficulty in extracting active principle from pancreas. George Walden, a chemical engineer employed by Eli Lilly then observed the importance of isoelectric point of insulin which helped in extraction of beef and pork insulin for commercial use.

In 1923, the Nobel Prize for the discovery of insulin was awarded to Banting and Macleod. Banting was outraged as the Nobel committee had ignored the significant contribution made by Best. He publically announced to share his prize money with Best and Macleod announced to share his award with Collip.

For almost 50 years after the isolation of insulin, only porcine or bovine insulin was available. The development of purified porcine insulin reduced the incidence of insulin allergy and development of lipoatrophy. Initially, crystalline insulin was available in concentrations of 10, 20, or 40 U per mL and, therefore, had to be taken with more than one shot in patients requiring large doses of insulin at a time. In 1972, U-100 insulin was made available which reduced number of injections to be taken and improved the patient compliance.

In 1936, Christian Hagedorn introduced the first “delayed-action” preparation of insulin. Subsequently, protamine zinc insulin (with controlled amounts of protamine), isophane insulin in 1946, and lente insulin (acetate buffering of zinc insulin) in 1952 were introduced. They had to be given twice a day and their introduction into the treatment regimen provided much better control than soluble insulin alone.

In 1958, Frederick Sanger was awarded the Nobel Prize in chemistry for his work on structure of proteins, especially that of insulin. He determined that the insulin molecule was composed of two different chains of amino acids held together by two bridges of sulfur atoms.

Other important milestones in the journey of insulin as available today have been highlighted in table 1.

Commercial production on human insulin was started using recombinant deoxyribonucleic acid (DNA) technology in 1982. Over next 2 decades, human insulin largely replaced older animal derived insulin.

Insulin lispro (rapid-acting) was the first insulin analog to be introduced followed by aspart and glulisine. Glargine was the first peakless basal insulin analog introduced in year 2001, shortly followed by the introduction of detemir.