Insulin: It was believed to exist, but everyone who tried to isolate it failed

The path to insulin isolation was anything but straight.

Insulin: It was believed to exist, but everyone who tried to isolate it failed
Banting FG, Best CH. 1922. The internal secretion of the pancreas. J Lab Clin Med. DOI: 10.1111/j.1753-4887.1987.tb07442.x

It was finally captured in 1921.

Many decades worth of medical observation and dissection showed that problems with the pancreas caused diabetes.

The classical symptoms are high blood sugar, glycosuria (excretion of sugar in the urine), ketosis (burning fat instead of sugar), seizures, and, if untreated, death.

It was discovered that animals who suffer from diabetes naturally lose their pancreatic islet cells, and in 1909, Jean de Meyer, and in 1913, Edward Sharpey–Schäfer, suggested that a hormone was secreted from the islet cells to control glucose metabolism and its uptake from the bloodstream.

Sharpey–Schäfer named this substance 'insuline.'

But, this is not the only function of the pancreas.

It also produces trypsin, an enzyme that helps digest proteins in the stomach.

This made things complicated because everyone who tried to isolate insulin ultimately failed because it was immediately chopped up during extraction by trypsin!

Fortunately, Frederick Banting, a Canadian surgeon, came across an article describing how the blockage of the pancreatic ducts in a patient resulted in the death of the acinar cells (the ones that pump out trypsin), but preserved the islets with no sign of the development of diabetes.

Banting, who had no formal scientific training, thought that a good way to isolate insulin might be to 'ligate' or tie off the pancreatic ducts to kill all the acinar cells and then grind up what was left over.

He pitched his grand idea to JJR Macleod, a professor of physiology at the University of Toronto, who had a lab and access to research animals.

Macleod was skeptical, but he was also going on vacation, so he gave Banting the keys to the lab, 10 dogs, and a coin flip determined that Charles Best would help Banting.

Best was also tasked with making sure the lab didn't burn down while Macleod was away.

7 dead dogs later, Banting and Best had perfected their technique, and generated the data that can be seen above.

What's displayed is two days worth of blood glucose readings (solid black line) from a dog whose pancreas was removed (causes diabetes).

The numbered circles are injections of ground up organ extracts: 1. Refrigerated ligated pancreas, 2. Liver, 3. Spleen, and 4. Fresh ligated pancreas.

Here you can see that ligated pancreatic extracts (1 and 4) cause a sharp reduction in blood glucose.

Insulin had finally been isolated!

Further work by James Collip revealed that highly purified insulin could be made from chilled pancreas (no ligation) and extraction in 90% ethanol.

This process was optimized by Eli Lilly for use on pig and cow pancreas which produced the majority of insulin until a synthetic was developed 56 years later in 1978.