A Question of Balance

Our Human Remains Conservator, Cat Irving, tells us more about the history of insulin.

Anyone with type 1 diabetes is familiar with the concept of balancing their blood sugar – weighing activity and food against medication. This is something I have lived with daily for nearly thirty years. It is a condition that is dealt with through medication and lifestyle, but people might not realise the important role surgery has played in the development of diabetes treatment.

We discussed diabetes in one of our previous pathology spotlights; in type 1 diabetes a misplaced immune response destroys the cells in the pancreas that produce the hormone insulin, responsible for regulating blood sugar. Blood sugar build up can cause damage to virtually every part of the body, and common complication include kidney disease, nerve damage, heart problems, eye problems, and stomach problems. Before the discovery of insulin this condition was a death sentence. The only treatment was strict diet containing no carbohydrates and less than 500 calories a day – effectively starvation.

Foot amputated after developing diabetic gangrene, a complication of prolonged high blood sugar levels. (Surgeons’ Hall Museums)

The cells that produced insulin were discovered by a German pathologist called Paul Langerhans – though he didn’t know what they did. In an 1869 paper on the histology of the pancreas he described islands of cells whose function he didn’t understand amongst the cells that produced digestive enzymes. They were named islets of Langerhans after him. What these cells did remained a mystery until the twentieth century. That removing the pancreas resulted in diabetes was established by the end of the nineteenth century, but in 1901 an American pathologist showed that degeneration of these islets of Langerhans cells led to the onset of diabetes. Attempts to identify the substance secreted by these cells was unsuccessful.

In 1920 a young Canadian surgeon called Frederick Banting was preparing to give a lecture on the pancreas at the University of Western Ontario, and was reading the latest journal articles on the subject. This got him thinking on the subject of how to further investigate the mysterious pancreatic secretion and how it was involved in diabetes. He approached a Scottish physiologist called John Macleod, an expert in carbohydrate metabolism who worked at the University of Toronto. Macleod had trained in Aberdeen, and had published papers on the presence of sugar in the urine in cases of diabetes. He wasn’t convinced that Banting knew all that much about diabetes, but he gave him some lab space, and assigned a research assistant to him called Charles Best. Their experiments enabled them to keep a severely diabetic dog alive. A biochemist called James Collip was brought in to help purify the pancreatic extract. In January 1922 a 14-year-old boy called Leonard Thompson became the first human to be successfully treated with insulin. In spite of this success, all was not well back in the lab: relations between Banting and Macleod became increasingly sour, with Banting convinced that Macleod wanted to steal his thunder for what was increasingly looking like an important discovery. In spite of this, on 3rd May 1922 Macleod made an announcement that they had discovered ‘insulin’.  Insulin went into commercial production with the pharmaceutical company Eli Lilly, and gave a new lease of life to diabetics. In 1923 Banting and Macleod were given the Nobel Prize in medicine. Banting was furious, believing he should share the prize with Best, not Macleod, and shared his prize money with Best, causing Macleod to do the same with Collip.

This is an insulinoma surgically removed from a 72-year-old man. An insulinoma is a pancreatic tumour which secretes insulin. (Surgeons’ Hall Museums)

While insulin can help a person with diabetes lower high blood sugar level, if too much insulin is given this can cause hypoglycaemia – when the blood sugar level is too low. Initially this can cause confusion and sweating, leading to seizures and coma. Hypoglycaemia had been recognised since the nineteenth century, but it was only after the discovery of insulin that excess production of insulin was recognised as causing this. A tumour, called an insulinoma, was found to be the cause of this. These tumours derive from the cells in the insulin-producing islets. In 1929, a 54-year-old female lawyer presented with a six-year history of convulsions and comas. It had been noticed that food – particularly high sugar food – could delay or stop these attacks. After attempts to manage the condition medically failed, she was referred to the surgeon Roscoe Reid Graham, based at the same Toronto University where Banting and Best had discovered insulin eight years earlier. He speculated that a tumour may be causing the problem, and proceeded with surgery. Little pancreatic surgery had been done at all to this point, but Graham managed successfully to find and remove what turned out to be an insulinoma. The patient recovered well, and lived without recurrence of symptoms for a further 23 years.

Fifty years later surgery for insulinoma changed the way diabetes was treated. The insulin that diabetics injected every day was, until that point, extracted from cows and pigs, with 56 million animals needed annually in the US alone to meet demands. Some patients had problems with allergies to pork or beef insulin. Insulin was the first protein to be fully sequenced, and synthetic versions were manufactured through the 1960s and 70s, but it was expensive. In 1979 a German scientist called Axel Ullrich obtained a sample from an insulinoma removed from a woman in Munich, and extracted insulin mRNA from it. He cloned this and inserted it into DNA of the bacteria E. Coli. This was the first time a human gene had been cloned, and the strain of E. Coli Ullrich produced would make insulin. Within a few years this human insulin would be used in diabetes treatment. This was not without problems – patients injecting human insulin where more likely to not recognise the symptoms of low blood sugar level, and it caused weight gain not seen when using animal variants. It did, however, allow for mass production of an affordable insulin, saving many lives. By 2001 95% of insulin users were injecting human insulin rather than animal derived products.

Rapid Acting Insulin (authors own)

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