Diabetes has a long history, with some references dating back to 1500 BC. This ancient disease, due to the short life expectancy, was synonymous with the visit of the Grim reaper. It changed only 100 years back when insulin was discovered. This discovery was thus a breakthrough in the history of medicine and saved countless lives.
Though the disease was very ancient, the biology of diabetes was poorly understood. Some of the earliest remedies for the disease included bizarre elements like jelly of viper’s flesh, broken red coral, and fresh flowers of blind nettles.
Fast-forwarding to the 19th century, dietary interventions were the norm. The diabetic patients were prescribed low calorie- low sugar foods, aimed at lowering blood glucose levels. The ‘Starvation diet’ popularized by two prominent American dietitians Frederick Allen and Elliott Joslin, went as low as 400 cal/day, and carbohydrates were virtually eliminated. Results indeed showed lowered glucose levels, but a calorie-restricted diet was difficult to follow and hazardous in the long run. Some of his patients could not stick to this strict diet and soon returned to their normal diet and died of diabetes. Others who religiously followed the stringent dietary regulations succumbed to starvation but lived longer lives. Nevertheless, Allen’s notorious dietary method did not last long as insulin was soon discovered.
The most critical discovery in the history of diabetology was perhaps discovering the role of the pancreas in diabetes. It was serendipity that led to this milestone discovery which would eventually lead to the discovery of insulin. Minkowski and Mering were studying the function of the pancreas in digestion. During their experiment, they removed the pancreas of the dog. The next day their lab assistant reported a swarm of flies flocking around the urine from the dogs. Intrigued by this observation, they analyzed the urine and found it loaded with sugar- a well-established symptom of diabetics. This hinted at a relationship between the pancreas and diabetes. The pair continued to carry out experiments revealing that secretions from the pancreas controlled sugar metabolism, thus establishing the role of the pancreas in diabetes. This discovery threw light on the fact that there is more to diabetes than increased levels of glucose in the blood.
Several scientists tried to use pancreatic extracts to cure diabetes as they seemed to reduce glucose levels but its administration led to several adverse effects like vomiting, fever, and even convulsions. The investigation by scientists pointed to the role of a cluster of cells known by the name of Langerhans Islands in glucose metabolism and the hypothetical substance from this area came to be known as “insulin”. Several scientists attempted to extract pure insulin from Langerhans Islands but in vain.
Frederick Grant Banting, a Canadian scientist while reading about pancreatic secretions devised an experiment to study the relationship between pancreatic secretions and diabetes. He approached MacLeod, professor of physiology at the University of Toronto, with his idea of extracting insulin. MacLeod was skeptical, he pointed out to Banting the many failures in insulin extraction by renowned scientists. He realized that Banting had only superficial textbook knowledge and showed little practical familiarity. Even so, MacLeod provided him with laboratory space and his student assistant, Charles Best.
Best and Banting ligated the pancreatic ducts of dogs which destroyed the enzyme secreting parts while retaining the islets of Langerhans. The pancreas was then removed, the internal secretion was extracted and administered to dogs made to be diabetic through pancreas removal. But to their dismay, the dogs died. They continued their experiments, but this time they chopped up degenerated pancreas into small pieces, placed it in Ringer’s solution, and partially froze the mixture. This mixture was then ground and administered to dogs. They noted a drop in blood sugar levels, but the improvement did not last long. Despite additional injections, blood sugar rose and the dog died. Though the experiment failed, it showed that they had isolated an anti-diabetic principle.
Best and Banting improvised their method by using secretin hormone to stimulate the pancreas to drive it to exhaustion, instead of duct tied dogs. The method yielded positive results but soon realized either method did not yield sufficient insulin. They went on to find another source: the fetal pancreas. It was known by then that the fetal pancreas was abundant in islets than other cells. They believed fetal extract could serve as a rich source of islet secretion that was least contaminated. Although this method was more productive, it was not industrially feasible due to limited raw material supply.
They improvised their method again by using a whole pancreas extract with alcohol, they no longer had to rely on duct-tied dogs or fetal pancreas for insulin extraction and the method showed significant therapeutic improvements in dogs.
They were joined on their quest by James Bertram Collip, a Canadian biochemist. Collip attempted to purify the isolated insulin. The research soon proceeded to clinical trials. The first clinical trial was on a 14-year-old severely diabetic patient, but no clinical benefit was observed. Collip worked on purifying insulin further which was administered to the same patient in the second clinical trial which turned out to be a success, with the patient showing remarkable improvement.
MacLeod and Banting were honored with the Nobel Prize in medicine but the efforts of Best and Collips went unnoticed. Following the receipt of the Nobel Prize, the pair divided the cash prize amongst the four of them as they felt it was the efforts as a team that led to the discovery.
The team with the help of Eli Lilly and Company started large-scale production of insulin, enough to supply entire North America. But the cure was not flawless, it caused allergic reactions in many. This led to the development of the first synthetic human insulin using recombinant technology marketed by Eli Lilly. Since then, insulin has come a long way with diabetic patients having multiple formulas and ways of delivery to choose from.
Written by Niloufer Shanavas
BS-MS dual degree programme