The Discovery of Insulin, Part 2

Published Mar 11, 2020, 1:00 PM

Last time we talked about how diabetes has been described through history, including treatment before the development of insulin. Today, we’re telling the insulin part of the story, which was at times fraught and contentious. 

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Welcome to Stuff You Missed in History Class, a production of I Heart Radio. Hello, and welcome to the podcast. I'm Tracy B. Wilson and I'm Holly Frying if you are just tuning in today. This is a two parter. It is on the development of insulin. And last time we talked about how diabetes has been described through history, including how people were being treated with starvation diets in the years just before the development of insulin, and today we are going to tell the insulin part of the story, which does build on research that we talked about last time around. This will the easiest to understand if you have heard part one. As was the case last time, we're going to be talking about how experiments on animals led to this discovery, as well as how the byproducts of animals that were slaughtered for food we're used to make insulin. It is not clear who coined the term insulin. It comes from the word insula or island, as a nod to the islets of langer Hans. As we talked about in Part one. The islets of langer Hans are cells in the pancreas that produce insulin and other hormones. Jean de Meyer of Belgium used the word insuline with an E on the end in nineteen o nine, and apparently independently of that, Ernest Henry Starling, who coined the word hormone, also used the word insulin with an E. Four years later. In the early nineteenteen, Sir Edward Albert Sharpie Schaffer also described a hypothetical substance secreted by the islets of langer Hans, which controlled the body's glucose levels, and he called that insulin. This time there was no E on the end. None of these people are the ones credited with the discovery of insulin, though that story starts with Frederick Grant Banting. Banting was born on a farm in Ontario, Canada, and initially he had planned to go to divinity school, but after enrolling at the University of Toronto, he's changed his major to medicine. When World War One started, he joined the Canadian Army Medical Corps and was placed on an accelerated medical study program. During the war, he was wounded in action and awarded the Military Cross in After the war was over, Banting completed a surgical residency and tried to set up a private surgical practice, it did not grow quickly enough for him to make ends meet, so he also took a part time teaching position at the University of Western Ontario that's now known as Western University. The classes that he was teaching included physiology, something that he had studied as part of his own medical education, but also something that he really needed to brush up on in order to teach. On October thirty one, nineteen twenty, Banting was brushing up on the pancreas he read a paper called the Relation of the Islets of Longer Hauns to Diabetes with Special Reference to Cases of Pancreatic Lithiasis by Moses Barron. This paper discussed the autopsy of someone you turned out to have a pancreatic stone that had totally blocked their main pancreatic duct. The person's pancreas still had islets cells, but the asiner cells had atrophied. This paper also noted earlier experiments in which the main pancreatic ducts of various animals had been partially or totally legated, which had caused similar results, and that is research that we talked about some of back in our previous episode. Banting was inspired by this idea. He wrote a note in his journal which read, quote diabetes legate pancreatic ducts of dog keep dogs alive till assony degenerate, leaving islets. Try to isolate the internal secretion of these to relieve glycosuria. So a few things to note at this point. One of the Banting's note is about glycosyria, or sugar in the urine, rather than blood sugar. Banting also was not really aware of all those experiments that we talked about in part one. He didn't really realize that rees As had spent more than two decades trying to do basically what he was describing without yielding something that was safe enough to use in human patients. It's also not clear how exactly that he thought he might quote try to isolate the internal secretion of the islets of langer huns, or whether he was thinking about preparing a pancreatic extract or thinking he might try to find the secretion itself. Later on, when he told people from memory what he'd written down in his journal that night, he said it was quote legate pancreatic ducts of dogs weight six to eight weeks for degeneration, remove the residue, and extract, and that is a lot more specific. Also, part of Banting's basic idea here was a little bit off. His rationale for causing the acid our cells to atrophy was that they produced digestive enzymes, and he thought those enzymes might destroy whatever vital substance was being produced in the islets of langer Huns. But really these enzymes are not active until they come into contact with other enzymes in the small intestine. The relationships between those two different sets of enzymes had been discovered back in nineteen o four. Also, it's possible that there's some other explanation, but his misspellings of both diabetes and glycosuria suggests that Banting wasn't all that familiar with what he was writing about. So at this point Banting went to his boss at the University of Western Ontario about this idea. His boss referred him to John James Rickard MacLeod at the University of Toronto. McLeod was born in Scotland and had studied medicine at the University of Aberdeen. He had also taught at several universities and institutes in Europe and North America before becoming professor of physiology at the University of Toronto and also director of its physiological Laboratory. McLeod was a leading expert in carbohydrate metabolism at the time, and in nineteen he had published Diabetes, Its Pathology and Physiology. He had been trying to identify which part of the nervous system controlled the liver's glycogen storage functions. Unlike Banting, McLeod knew all about those earlier attempts to make a pancreatic extract that could treat diabetes, and he thought there was some kind of pancreatic secretion that could be the key to an effective treatment, but he had his doubts about it's ever being isolated and used. And it wasn't just that McLeod had doubts about whether it was possible at all to make a usable pancreatic extract. Those earlier researchers also all had training and skills and experience that Banting just didn't have. Mcloud's impression of Banting was that he had a very basic, textbook level understanding of the pancreas and its role in diabetes, and really this was pretty accurate. So McLeod was reluctant to offer Banting the lab space, assistance, materials and animals that he was going to need to research his idea. The two men had multiple meetings to talk through the situation, and then when McLeod finally agreed to let Banting do some experiments over the summer, Banting actually got a little nervous about it. Banding still thought that his idea might lead to a breakthrough, but he also understood that if he left his practice and his job to pursue an idea that didn't work out, he would basically have to start his career over while also trying to pay off debts from a failed project. On March eighth, one, Banting and McLeod finally agreed on the terms of the project. The work would take place over the summer of nine starting in mid May. Two students, Charles Best and Edward Clark Noble, would assist Banting. They would divide the summer between the two of them. These two young men flipped a coin to see who would take the first shift with Banting, with Best planning to take the first half of the project and Noble planning to take the second half. Best at that point had finished his bachelor's degree in physiology and biochemistry and was preparing to start medical school. For about a month, Banting, Best in McLeod all were together in the lab, with McLeod fine tuning their plan and process and surgical techniques and instructing them on how to best prepare an extract. Then in mid June he left for a vacation in Scotland that he had previously arranged. We will talk about how Bantings and bests work proceeded over the summer, which will have more about their animal experiments after a quick sponsor break. When Frederick Banting and Charles Best started their experiments on dogs to try to find a treatment for diabetes, things did not go well. Their plan was to legate the pancreatic ducts of some of the dogs, which would cause the assent our cells to atrophy, but theoretically at least leave the islets of longer hunts mostly unaffected. By that point, Banting would have learned that the digestive enzymes were inactive while they were actually in the pancreas. But this atrophy of the assenter cells would at least in theory, deuced the amount of material that needed to be removed from the extract before it could be safely used. Once enough time had passed after this legation procedure to allow the asdenter cells to atrophy, they would euthanize the dog and remove its pancreas, using it to prepare an extract. Then they'd inject that extract into another dog whose pancreas had been removed entirely. However, these surgical procedures could be difficult. It was also summer, so the facilities where they were working were hot and uncomfortable. Several of the dogs that they were working with died of infections or other complications, and they started buying stray dogs as replacements. It was mid July before they had a deep pancreatized dog and one with an atrophied pancreas ready to work at the same time. The process of preparing a pancreatic extract was also long and complex. It included chopping the pancreas, chilling it, grinding it up, filtering it, and warming it back up to body temperature. On July, they tried injecting their extract for the first time. Although the sugar levels in the dog's urine did drop, they rose again pretty quickly. The dog died the next day, most likely from an infection. Banting and Best kept trying, though. When Edward Noble came back to the lab to take over his shift as assistant, he found that the two of them had worked out this whole rhythm and flow to their work. At that point, Noble thought that if he tried to take Best's place, as was previously planned, he would just become a hindrance to the project. He would have to learn everything that Best was doing pretty routinely at that point, so he left Best to it, although he did come back to the project later on, which we will get to. In August, Banting and Best ran out of legated dogs, so they switched to using the whole pancreas something that, as it turned out, worked just as well. They kept refining their work and taking notes, and when McLeod returned to the lab on September one, they had results. This seemed promising. They were still seeing some complications, but their extract did seem to be lowering the glucose levels of deep pancreatized dogs. McLeod, as we said earlier, was very skeptical about this whole project from the very beginning, and he was surprised enough at these results that he questioned whether they were accurate. Banting was highly insulted by the suggestion, and the two men butted heads over it. Ultimately, McLeod told them to repeat their experiment. Apart from taking offense at being questioned about the accuracy of his work, Banting was also worried about his finances. He had planned to take the summer to do this research, but he had not planned for it to continue into the next academic year. He also thought the facilities where he'd spent the summer working left a lot to be desired. For example, he said that they couldn't scrub the floors thoroughly because if they did, water leaked through the ceiling of the room below. He thought that was to blame for some of the infections and the deaths of their research animals. So Banting asked for a salary and one for best as well as repairs to the floor of the lab and an assistant to take care of the animals. Banting also asked for a biochemist to be added to the team to help them better refine their pancreatic extract. McLeod didn't think they were ready for that last step yet, but he did give Banting and Best retroactive salaries. He also hired somebody to take care of the dogs and arranged to have the laboratory floor waterproofed with tar, which was like the least expensive way to deal with this water seepage problem. Eventually, Banting and Best tried another source for their pancreas tissue. After learning that fetal and newborn calves had proportionally more islet cells than older animals do. They started buying fetal pancreas from slaughterhouses. They still had trouble getting enough pancreas for their work, though, so they ultimately started using the whole pancreas of adult animals, also purchased from slaughterhouses. In November of one, Banting and Best published a paper, the Internal Secretion of the Pancreas. Banting also presented the paper publicly that December in New Haven, Connecticut. This presentation once again caused tension between Banting and McLeod. Banting was just not a very good public speaker, and some of the people who were in the audience on that day were literally at the top of their field. He just didn't have the breadth of knowledge to answer some of the very probing questions that they asked him. When Banting had trouble fielding questions, McLeod stepped in. He did have that breadth of knowledge, and he was also polished and well spoken in his presentation. He also used the word we a lot, something that wasn't necessarily unusual considering that the work was happening in his lab ultimately under his supervision. But Banting felt like McLeod was taking credit for work that he had not actually done. And the audience that day was the research director for Eli Lily Pharmaceuticals, who asked if the company could be involved in this project, and in McLeod's opinion, once again, they were not there yet. By the end of though, McLeod thought the project was promising enough that he finally did bring on a biochemist, James Bertram Collop, who took a sabbatical from the University of Alberta at Edmonton to work on it. McLeod also dedicated the whole lab to the project, thinking that they were on the verge of a life saving breakthrough. The extraction method that Collip developed was a lot more effective but also still very involved. I initially had like all of the steps written into this outline, and it went on for paragraphs. He realized that different pancreatic materials could be extracted at different strengths of alcohol, and so he developed this method that included multiple extraction steps, with the results of those extractions being concentrated in centrifu, huged and precipitated. It went on. He also discovered that the extracts lowered the blood sugar of rabbits, so they no longer needed to work with deep pancreatized dogs. Edward Clark Noble rejoined the project at this point to help with the studies on rabbits. Running parallel to this work at the University of Toronto were developments in blood sugar testing, which made it easier to test their extracts effects on blood sugar directly, rather than relying on how it affected glucose levels in the urine. More efficient and effective blood sugar testing was a huge part of the ongoing development of insulin. In late December of Banting tried one of their extracts on a human subject. Dr Joseph Gilchrist had been one of Banting's classmates and had developed diabetes not long after they graduated from medical school. This extract did not work at all, though, and it wasn't because the extract itself was bad. Even if they had made completely pure insulin, if taken orally, that would have been digested in the stomach way before it could have been absorbed into the bloodstream. In January of the team was ready for their first attempt at injecting their extract into a human patient. The patient was Leonard Thompson, who was fourteen years old and critically ill. He weighed only sixty five pounds that's about thirty ms when he was admitted to Toronto General Hospital. He had been on a starvation diet like we talked about in Part one, which had taken him down to about four hundred fifty calories per day. His daily yearine output was about four leaders that's more than a gallon. A typical amount is more like eight hundred to two thousand million leaders. And he was also showing signs of diabetic keto acidosis, which is when the body starts burning fat instead of sugar for fuel and as a result, acids start to build up in the blood stream. So this whole time Banting had felt like McLeod had been stealing credit for his work, second guessing him, and undermining him every step of the way. Added to all of that, Banting could not really control this first human trial at all. He did not have the background or the experience that was needed to run a trial on human subjects. He also did not have the authority to work with patients at Toronto General Hospital, So when it came to their first human trial, Banting really insisted that they use an extract that he and Best had prepared. They did this on January eleventh. Of This preparation did lower Leonards blood sugar somewhat, but it did not alleviate any of his outward symptoms of diabetes. The boy also developed an abscess at one of the injection sites. Colip, who was still refining his methods for extraction, really went into overdrive at this point, finally producing an extract he thought was pure enough to use. Several days later. They tried again with this extract on January twenty three of nineteen twenty two, and this time the results were immediately and dramatically affected. Leonard's blood sugar dropped significantly, as did the glucose in his urine, and he also was just visibly improved. It was obvious to other people that he was doing better. In the words of Charles Best's notes quote, daily injections of the extract were made from January to February fourth, accepting January and February fourth. This resulted in an immediate improvement. The excretion of sugar became much less, the acetone bodies disappeared from the urine. The boy became brighter, more active, looked better, and said he felt stronger. Leonard, whose condition had been critical when he was admitted, lived another ten years. After the success, though, the ongoing backbiting and hostility in the lab became even more dramatic, and we will get to that. After another sponsor break at Leonard Tom Sin was getting his first injections of a working pancreatic extract. The already contentious relationships among the team from the University of Toronto got even worse. James Callip, who had not shared the details of his extraction method with anyone else, threatened to quit the project and patent it himself. The details here are a little bit sketchy, but Banting was outraged and he and Collip had a physical altercation in the lab, with Banting grabbing Collip by the color of his coat and slamming him into a chair, and Best writing that he had to restrain Banting with all of his force. After this, on January two, Banting, Best, and call Up all signed a memo that none of them would be seeking a patent for insulin. This was part of a manufacturing agreement with Connu Laboratories, which is a public pharmaceutical company that had been established in Canada during World War One to make diphtheria anti toxin. After that first successful treatment of Leonard Thompson, six more patients were treated in February of nineteen two. From there, they moved quickly into a clinical trial, and at that point the project largely moved out of Bantings and Best's hands. As we said earlier, Banting just did not have the training or experience to run a clinical trial on human subjects, and he was deeply frustrated by his exclusion, and he tried to cope, unfortunately by drinking to excess. On March two of nineteen twenty two, a paper was published in the Canadian Medical Association journal called Pancreatic Extracts in the Treatment of Diabetes melitists. It's authors were F. G. Banting, C. H. Best, J. B. Collip, W. R. Campbell, A. A. Fletcher, J. J R. McLeod, and E. C. Noble. The two names from that long list of authors that we haven't mentioned specifically before this point our Campbell and Fletcher, and those were the doctors who administered the actual injections to the diabetes patients. On May third, nine two, McLeod presented a paper called the Effects Produced on Diabetes by Extracts of Pancreas. It described that extract as insulin, once again from the Latin route for islands and apparently not related to the earlier uses of the same term from the same source. Both Banting and Best refused to go to this presentation. Between roughly these two papers, between March and May, the clinical trials of insulin had run into a huge stumbling block When Connaught laboratories tried to replicate Collips extraction methods. It just didn't work. Multiple sources described this as Collip losing the knack for making insulin, or as problems with translating Collips small scale batches from the laboratory into a large scale production. They finally did resolve the issues and started production in mid May of ninety two. For Banting's part, he believed that Collip had wanted to keep his method secret for his own benefit, and that consequently he had not kept good enough records, and that that's why they were having so much trouble. One patient died during this shortage, and Banting and call Up had another massive altercation. As words started to spread about insulin, families started trying to get their children included in the clinical trials. The most famous of these patients was Elizabeth Hughes, who was daughter of former New York Governor Charles Hughes. Her father, Charles later became Secretary of State in nineteen twenty one and Chief Justice of the U. S. Supreme Court. Elizabeth had been born in nineteen oh seven and had developed diabetes in nineteen nineteen. Elizabeth had been one of doctor Frederick Allen's patients and had been on a starvation diet before starting insulin therapy. Alan saw her at a conference later in nine two, and she was so improved that he literally did not recognize her. She later wrote. Quote Dr Allen said, with his mouth wide open. Oh, and that's all he did, and after starting insulin therapy, Elizabeth lived until the age of seventy three. Soon there was so much demand for insulin that cannot labs could not produce enough on their own, and that is when Eli Lilly and Company was brought on to increase the output. This led to yet another challenge, which was trying to standardize this treatment across two different drug makers who were operating in two different countries. It wasn't yet possible to measure the strength of insulin itself. You had to administer a sample of it to rabbits and then measure the rabbits blood glucose levels to figure it out. One issue in this whole process turned out to be because the two drug makers were using different sized rabbits, with one of them using rabbits that had been fasted and the other using rabbits that had been fed normally. He seemed like such small but important details, very very important details. Uh. This standardization process ultimately led to the first deaf nition of a unit of insulin, which was the amount that it took to lower the blood sugar of a rabbit weighing two kilograms from zero point one to zero point zero four five, with that drop happening over five hours and the rabbit having been fasted for twenty four hours. Insulin is still measured in units today, but we can also measure insulin itself now, so today one unit is equivalent to thirty four point seven micrograms of crystalline insulin. Throughout the nineteen twenties, Connaught Laboratories, ELI Lily, and numerous doctors, clinicians, researchers, and others were working on standardizing insulin, with one of the major contributors being Sir Henry Dale. Sometimes he's described as being the person who did it, but like there were a lot of people and entities involved. Another big project, including most of these same basic entities, was refining the extraction process and improving the yield of that process over a few year or as drug manufacturers went from being able to extract fifteen units of insulin from a kilogram of pancreas to extracting almost four hundred units per kilogram. In late nineteen twenty two, George Wilden at ELI Lily developed a method for isoelectric precipitation of insulin, but the relationships among banting best McLeod and call up, we're not nearly as productive. In September of nine two, hoping to create a definitive account of the discovery of insulin and put all of the arguing to rest, Colonel Albert Gooderham asked Banting, Best in mcleoud to each right up their account of what happened. By that point, coleb had returned to the University of Alberta at Edmonton, but McLeod wrote him and asked for his thoughts. This whole process did not really resolve anything, though. Banting characterized McLeod as constantly undermining and criticizing him and taking credit for his work, and he ended his write up with an appendix of six additional is that he said showed quote a lack of trust and cooperation on mcloud's part. McLeod characterized his caution as very reasonable, giving bantings and experience, and he pointed out that he had frequently taken a lot of care to give credit to Banting and Best whenever that credit was due. Best's account was relatively brief and fairly neutral between the two of them, although Banting, Best, and McLeod had all agreed not to personally apply for patents on insulin as part of their agreement with Connent Laboratories. Patents were needed to ensure quality and safety. This was a brand new drug that could be life threatening if made incorrectly, not just because of all the side effects that we talked about earlier from poorly made extract, but because of formulation that was too weak or too strong could be life threatening for patients. At the same time, the goal was to make insulin widely available as quickly as possible and for it to be affordable. An in Culin Committee had been established in early nineteen twenty two to help coordinate patenting and licensing issues. Numerous patents were issued on insulin and the process for making it in the early nineteen twenties. By nineteen twenty six, insulin was patented in twenty six different countries, and it had become the standard of care in managing type one diabetes, especially around the world. The relationship among those men who had created it was never smooth, though in many ways. Banting became the face of the discovery. On August nineteen twenty three, he was on the cover of Time magazine. He received numerous awards and honors, and he met King George the fifth. The Banting and Best Chair of Medical Research was established at the University of Toronto, and Banting was the first person appointed to it. However, none of that seemed to outweigh Banting's feelings about another award, which was the nineteen three Nobel Prize and Physiology or Medicine, which was awarded to both him and McLeod. Banting was so outraged at McLeod's inclusion and getting the Nobel Prize that he threatened to decline the award until somebody pointed out to him how unfortunate it would be for the very first Canadian Nobel laureate to refuse the honor. Banting ultimately decided to give best half of his prize money, and McLeod gave half of his prize money to call it. The team also faced criticism from a number of directions in the early nineteen twenties. Anti vivisectionists objected to the research in general, and to Banting's admission that they had been buying stray dogs off the streets when they ran out of research animals, some of which may have actually been people's pets. Within the medical community, there were people who criticized the whole project because even though it had a good outcome, it had started with Bantings fundamentally incorrect ideas. And then there was Nicolay Paul Askew, who he talked about briefly in Part one. He claimed aimed that Banting and McLeod had stolen his work and that they had only become known as the people to discover insulin because they had just made the first commercially viable extract. Poliscue had sent Banting his papers in ninety one and had asked him to keep up a correspondence with him, but Banting had never answered him. Banting and Best had also mischaracterized some of Poliscue's earlier work in their own writing, something that really seems to have been because of a mistranslation of a document that was in French, rather than a deliberate misstatement on their parts, like trying to cover something up. And we should also know that there are still people who make the argument that Polisque should be credited as the discoverer of insulin, while others point out that he also published multiple anti Semitic documents and that he helped found anti Semitic parties that later formed the fascist organization known as the Iron Guard in Romania. In a strange turn of events, the one collaborator that Banting was actually on good turn arms with at the end of his life was James Collop, who he had shoved into a chair earlier in this story. By the time Banting died in nineteen forty, he had fallen out with Best, who he had previously been close to. That year, being nineteen forty, Best was scheduled to travel to Europe to act as a medical liaison during World War Two. He canceled that trip and Banting took his place, reportedly telling a friend just before leaving, quote, if they ever give that chair of mine to that expletive deleted Best, I'll roll over in my grave. Having made that statement, Banting's flight on this trip crashed after taking off from Gander Bay, Newfoundland, on February nineteen forty. Banting survived the actual crash, but died of his injuries before he could be rescued. In terms of the other three of those first four contributors, Charles Best did succeed Banting as the chair of the Banting and Best Department of Medical Research. He continued to do groundbreaking work on insta land and he was part of the development of the drug heperin. He died on March thirty first, nineteen seventy eight. John McLeod left the University of Toronto for the University of Aberdeen in ninety eight, and he died in nineteen thirty five at the age of fifty nine. James Collup ultimately became the Dean of Medicine at the University of Western Ontario. He died on June nineteenth, nineteen sixty five. There have been a lot of developments in the worlds of endo chronology, diabetes and insulin since the nineteen twenties. That first preparation made in nineteen twenty two only lasted for about six hours and people could have really dramatic spikes and blood sugar as it wore off. He had to be really careful with it, so researchers started trying to develop versions of insulin that would be absorbed more gradually and predictably and would last longer. Researchers also worked on isolating insulin itself and figuring out its exact chemical structure. John j Abel crystallized insulin and nineteen twenty six ten years later, insulin was combined with the hormone protomine to make a version that was absorbed more slowly and consistently. In nineteen thirty nine, a version that combined protomine and zinc was introduced that could last for up to forty eight hours. Slow acting, buffered lente insulin's were developed in the early nineteen fifties. Beyond McLeod and Best, multiple other researchers have been awarded Nobel Prizes for work that was related to insulin. In nineteen fifty five, Frederick Sanger was awarded the Nobel Prize in Chemistry for his work in identifying the amino acids that make up a molecule of insulin. In nineteen sixty four, Dorothy Mary Crowfitt Hodgkin was awarded the Nobel Prize and Chemistry quote for her determinations by X ray techniques of the structures of important biochemical substances. One of those important biochemical substances was insulin. Then, in nineteen seventy seven, rosalind Yellow was one of the recipients of the Nobel Prize in Physiology Your Medicine Quote for the development of radio immuno assays of peptid hormones. This was tied to a discovery that people who got injections of hormones, including insulin, could develop antibodies to that hormone. Those two decades saw a lot of other advances in addition to those Nobel prizes. You're in glucose self test strips were introduced in the nineteen sixties. In nineteen sixty three and nineteen sixty five, two different teams each synthesized insulin for the first time. The first insulin pump was also developed in nineteen sixty three, although at the time it required a pump the size of a backpack. Amy's Diagnostics introduced the first blood glucometer in nineteen sixty nine. The first fully synthetic insulin was introduced in nineteen seventy five, was made using recombinant DNA rather than by extracting insulin from animal pancreas. Before this point, it took an estimated twenty steers or eighty hogs to get enough insulin for a patient for one year, and although most people are using synthetic insulince now, animal sourced insulin is still made today and there are still people who are using it to manage their diabetes. The ability to synthesize insulin made it possible for researchers to create insulin analogs in the nineteen eighties and nineties. These have slightly different amino acid chains from human insulin, so they lower blood sugar the way that insulin does, but they also behave a little bit differently in the body. In most cases, they're made to be absorbed more quickly or more slowly than human insulin. Is this research into ways to improve insulin is ongoing, including attempts to make insulin that can be administered orally. In the United States, there have been a lot of headlines about how expensive insulin has become, and a big reason for that is that all these refinements and synthetic analogs and other developments, they're all patented and so drugmakers can set their own price, and especially with these newer versions, there's just not a generic alternative available. In general, the lower cost alternatives that are available we're developed decades ago, so they haven't had all those tweaks and things like absorption rates that we just talked about. Using insulin to manage diabetes is a lifelong, daily process and researchers are still trying to find a way to treat diabetes directly, rather than using insulin to manage its effects. This can include pancreatic graphs or transplants, or finding a way to prevent the body's immune system from damaging the pancreas in the first place. The introduction of insulin also made it possible for people with diabetes to live much longer, so research is ongoing into ways to treat and prevent the complications that can arise later in life, including retinopathy, neuropathy, and foot problems. So that in two parts is insulin? Yeah? Uh, you did some listener mail on part one? Do you have some more for part do I do? It is from Ian. Ian sends a note about Woolworth's lunch counters, and Ian says, Hi, ladies, thank you for your episode on the lunch counter sit ins. Although it does feel funny to say thank you for an episode which essentially involved people being nasty to each other for something they did not choose, like the color of their skin. If you want to have lunch at a Woolworths lunch counter, you can still do so. If you visit Sydney, Australia. The Woolworths at town Hall Station still has a lunch counter on the top floor of its store. It's not quite the same Woolworths though. Many years ago I got a new workmate who had just moved from South Africa to Australia. He told me his wife had worked as a store manager for Woolworths in South Africa, but that it wasn't the same store as the one we had in Australia, so I looked it up out of curiosity. The original woolworth was founded in eighteen seventy nine and Utica, New York by Frank Winfield Woolworth. The store name was either Woolworth without an S on the end, or with and an apostrophe and an S on the end. It was originally a discount five and dime store, specializing in selling items five to ten cents, and grew to become at one time the largest department store chain in the world. The podcast Useless Information did a Christmas special last year that talked about how it popularized Christmas tree decorations in the US. Sadly, changing times in competition from new stores like Walmart led to its decline in the original Woolworths department stores were closed and the parent company focused on its foot locker brand instead. Woolworths did, however, set up several overseas subsidiaries in Mexico, Germany, Austria, Cyprus, Britain, etcetera. The German and Mexican subsidiaries still survived, but the British chain went out of business in two thousand nine. This was kind of sad, as Woolworths was a British institution. My mom even worked in one when she was in high school in England in the nineteen sixties. Meanwhile, back in some Australian businessmen want to set up their own woolworth style store. They had one or two ideas for the name, but they found the name Woolworths had not been registered in Australia, so they copied the name. Note this spelling has an S on the end and no apostrophe. Wolworths Australia started as a department store, but after World War Two started selling groceries and developed its own supermarket chain. Eventually, the department stores were rebranded as Big w for Big Woolworths and continue today, competing with the discount department stores like Target and Kymart. Woolworth's and its arch rival Coals are two big supermarket chains in Australia and control something like eighty percent of the market. It continues on from there, but the part about the Australian Woolworths was the part that I really wanted to read because I found that all very interesting. Thank you so much to Ian for writing in about that. Something that we didn't really mention in the episode or in any of the listener mail at this point is that a lot of the former Woolworth's buildings have been converted into something like the building is still standing with the original historic Woolworths facade on there um. And one that I have been to is now the Woolworth Walk in Asheville, North Carolina, which is like an art and studio space that also has a fifties style lunch counter in there. So if you'd like to write to us about this or anither podcast or a history podcast at iHeart radio dot com and then we're all over social media at missed in History. That's where you'll find our Facebook, Twitter, Pinterest, and Instagram, and you can subscribe to our show on Apple podcast The iHeart Radio app, and anywhere else to get your podcasts. Stuff you Missed in History Class is a production of I heart Radio. For more podcasts from i heart Radio, visit the iHeart radio app, Apple Podcasts, or wherever you listen to your favorite shows.

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