Diabetes and the discovery of insulin in 1920

1. Diabetes and the discovery of insulin in 1920 by Frederick Banting and Charles Best, Toronto, Canada

2. Type I diabetes mellitus • (lack of insulin; le miel = honey) • Symptoms: always hungry and thirsty, glucose in urine, tired, blurred vision, extreme weight loss. • Prognosis: slow, painful death, delayed by low carbohydrate diet. • Reason: digestion by carbohydrases converts all the eaten carbohydrate to glucose, and 100% is absorbed from the small intestine to the blood. But, in the absence of insulin, the cells are unable to take up (and use) the glucose for respiration.

3. Excess unused glucose accumulates in the blood and is flushed by the kidneys out into the urine, using lots of water and making the patient constantly thirsty. Dogs whose pancreas had been cruelly removed survived a long time on a diet of small molecules that did not need to be digested before being absorbed into the blood stream. But the dogs turned diabetic (sweet urine). Hypothesis: the pancreas produces something that is lacking in diabetics.

4. Blocking the pancreatic duct using a ligature stopped the flow of digestive enzymes (amylase, lipase, and the protease trypsin) to the small intestine. But the dogs did not become diabetic. Hypothesis: the pancreas secretes an unknown substance (insulin) directly to the blood.

5. Search for insulin: pancreas was mashed up and the soluble extract was injected into dogs that were made diabetic by removing the pancreas. Result: the pancreas extract did not cure diabetic dogs. Explanation: the hormone insulin is a protein that was digested (destroyed) by the trypsin (proteinase) from the pancreas.

6. Observation: ligated pancreas lost the ability to produce trypsin. Hypothesis: active insulin can be isolated from ligated pancreas. Prediction: injecting “insulin” into the blood should reduce the level of blood sugar in diabetic dogs.

7. Sterilising the pancreas extract before injection into the bloodstream • Meat extract is full of bacteria and possibly also viruses • Insulin is destroyed by boiling • Bacteria can be filtered out using sintered glass filters

8. It worked!

9. It also worked for humans, but they very quickly produced a serious allergic reaction against the pancreas extract from the dogs. Only when insulin was purified (i.e. everything but insulin was removed) could it be given repeatedly to humans. Only minute quantities of insulin could be prepared from tied up dog pancreas.

11. Later, larger quantities of insulin were produced from foetal calf pancreas that had not matured to produce trypsin. • Insulin was always in short supply, and diabetes increased. • Calf insulin is slightly different in its amino acid sequence from human insulin. Because of this it does not work perfectly in humans, and it may even be destroyed by our immune system (like a pathogen in a vaccinated person). • Insulin from animals was also feared to transmit mad cow disease and dangerous viruses. USA

12. Just when the world was running out of calf insulin, it became possible to produce • human insulin • guaranteed free of disease • in unlimited quantities • by putting the human gene for insulin into a harmless bacterium by • genetic modification.

13. Transplanting a pancreas from another person does not seem possible, but In the future, it may become possible to re-grow a functioning pancreas from your own stem cells. • Such a replacement pancreas would be accepted by your body without the need to take unpleasant and expensive immuno-suppressant drugs. • A replacement pancreas would control the level of blood glucose better than is currently possible with insulin injections; i.e. blood glucose homeostasis would be better regulated. • The fertilised egg is the ultimate stem cell because it has the potential to develop into every type of specialised body cell (e.g. nerve cell, muscle cell etc.).

14. The total number of people in this world with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030 =4%of the population doubling in 30 years!

15. Questions about the discovery of insulin • Who discovered insulin? • When was insulin discovered? • Why are untreated diabetics hungry even after they have eaten pasta? • Why does the blood glucose level increase in diabetics? (2 reasons) • How could dogs survive without a pancreas and what diet should they be given? • Why did ligature of the pancreatic duct not make the dogs diabetic? • Why was insulin, the chemical substance, so difficult to discover? • Why does insulin need to be injected into the blood stream? • What needed to be done before animal insulin could be used for humans? Explain why. • How could insulin preparations be sterilised (made free of bacteria and viruses) to prevent harmful bacteria being introduced into the blood (blood “poisoning”)? • What was the source of insulin before the advent of genetically modified (GMO), insulin producing bacteria. • Would you prefer insulin made naturally by animals to GMO insulin? List advantages and disadvantages of both. • What would happen if we could no longer use insulin from GMO bacteria? • Should stem cell research be allowed? Give arguments for and against.

16. Dorothy Hodgkin 1910-1994 Sir John Leman Grammar School, Beccles, Suffolk. Universites: Oxford and Cambridge 1964 Nobel prize for developing protein crystallography and determining the position in 3d of every single atom in the hormone insulin.