The story of the discovery of the hormone insulin, the elucidation of its role in controlling blood sugar levels and its development as a successful treatment for diabetes is a rich vein in the history of biochemistry and molecular biology — as outlined by Henry Miller the journal American Council Science and Health recently.
Hormones are chemical messengers that affect/control many bodily processes. Insulin plays a key role in regulating blood sugar levels — a lack of insulin or an inability to react adequately to insulin causes the disease of diabetes. Most body cells rely on insulin to absorb glucose from the blood.
Glucose is the body’s main source of energy, and the brain relies exclusively on it. Insulin, released from the pancreas, signals muscle, liver, and fat cells to absorb glucose, which rises in the blood after we eat a meal. This glucose is “burned” in our cells to generate energy. When the body has sufficient energy, insulin signals the liver to store glucose as glycogen.
Chemically insulin is a small protein. Proteins are made of amino acids, of which there are 20 kinds. The insulin molecule comprises 51 amino acids strung together in two chains, one 21 and the other 30 amino acids long. The two chains are joined together by disulphide bonds. The amino acid sequence of insulin was elucidated by biochemist Fred Sanger in 1953, for which he received the Nobel Prize in Chemistry in 1958.
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There are two forms of diabetes — Type 1 and Type 2. In Type 1 diabetes the body produces too little insulin and many cells can’t absorb enough glucose from the blood. The body must therefore use other sources of energy, which leads to dangerous complications. Type 1 diabetes is successfully treated by insulin injections or delivery by insulin-pump.
In Type 2 diabetes, also known as Resistance Diabetes, body cells are resistant to insulin and less well able to absorb glucose from the blood. Depending on the level of insulin resistance, Type 2 diabetics may also take insulin injections to manage blood glucose levels.
In 1922 Dr Frederick Banting, medical student Charles Best and biochemist Bertram Collip, supervised by Prof John McLeod, Toronto, produced a crude preparation of insulin from cow pancreas and showed that it helped diabetic dogs to regain health. After further purification, this insulin was used to treat a 14-year-old boy Leonard Thompson with Type 1 diabetes.
Before this, Type 1 diabetics would only have months, a few years at most, to live. Leonard lived for a further 13 years before unluckily succumbing to pneumonia. Banting and McLeod were awarded the 1923 Nobel Prize in Physiology or Medicine for this work. They shared the prize money with Best and Collip, feeling they were equally deserving of recognition.
Pharmaceutical company Eli Lilly then entered the picture and quickly developed a method for higher purification of insulin from pigs/cows. More than two tonnes of starting material was required to produce 8oz of purified insulin. But by the early 1970s, a problem emerged. Supplies of animal pancreases declined and the prevalence of Type 1 diabetes grew, precipitating fears of insulin shortages.
Fortunately, at this time a new powerful tool called Recombinant DNA Technology (genetic engineering) became available, promising to produce insulin in unlimited amounts, insulin that, unlike insulin from animals, was identical to human insulin.
Genetic engineering was employed to insert the gene for human insulin into a bacterium. The bacterium then multiplies producing insulin and simply by inducing the bacteria to multiply freely, virtually unlimited amounts of human insulin can be produced. Insulin was the first genetically engineered drug.
Eli Lilly immediately saw the potential of this technology. They obtained genetically engineered insulin-producing E.coli bacteria from biotech start-up Genentech and developed processes for large-scale cultivation of these bacteria in huge fermentation vats to be used for the purification of human insulin. Eli Lilly’s product was pure and identical to human insulin. The product performed brilliantly and the small minority of patients who reacted adversely to animal insulin tolerated the human variety well.
The United States Food and Drug Administration granted marketing approval to Eli Lilly for the new product in 1982 after only five months assessment of their application. However, since that time, regulators have become extremely risk-aversive. Bringing a new drug to market now takes an average of 11 years and costs an average of over $2.5 billion (€2.4 billion).
- William Reville is an emeritus professor of biochemistry at UCC
