Hello, welcome to the session The Discovery of Insulin Revisited, Lessons for the Modern Era. I'm Dossie Trentz and I'll be serving as your moderator today. This is particularly an important topic given that we are celebrating a decade from not just the discovery but also the applicability of insulin as a treatment for diabetes mellitus. We are delighted to have as our presenter today Dr. Gary Lewis. Dr. Lewis completed his medical training in 1982 at the University of Witwatersrand in South Africa, followed by then specialty training in internal medicine and then endocrinology fellowship at the University of Chicago. He joined the staff of Toronto General Hospital in 1990, was appointed head of the Division of Endocrinology at University Health Network and Mount Sinai Hospitals in 2001, then was appointed director of the University of Toronto Division of Endocrinology and Metabolism in 2008, and then director of the Banting and Best Diabetes Centre, University of Toronto in 2011. He is a full professor in the Department of Medicine and Physiology, University of Toronto, and he holds the Sun Life Financial Chair in Diabetes and the Drucker Family Chair in Diabetes Research. Dr. Lewis has made a number of critical discoveries elucidating the mechanism of blood fat abnormalities in diabetes and pre-diabetes states. He has been awarded and honored by multiple national and international organizations. He's been invited to present research findings at many universities around the world and certainly at many international meetings. Dr. Lewis is a principal investigator of Diabetes Action Canada, one of the chronic disease networks funded through the Strategy for Patient-Oriented Research Initiative, and he undertakes translational research with very active patient engagement. Dr. Lewis, please. Thank you for that kind introduction, and thank you to the organizers of this meeting for inviting me to give this lecture on the discovery of insulin 100 years ago at the University of Toronto. So prior to the discovery of insulin in 1921-22, type 1 diabetes was not only universally and uniformly fatal, but it was an absolutely shocking illness. Here you can see a tragic photograph of a young girl just wasting away, it looks like a concentration camp survivor, and this was prior to the availability of insulin. So before then, there were a number of diets that were advocated as treatment for this condition, and particularly very restrictive carbohydrate diets that were very difficult for people to follow. They would maybe achieve survival for just a few months, but ultimately, without insulin, one would succumb to type 1 diabetes. I'm going to read you this really wonderful excerpt from this book, The Discovery of Insulin, by Professor Michael Bliss, the late Professor Michael Bliss, published in 1982. The discovery of insulin at the University of Toronto in 1921-1922 was one of the most dramatic events in the history of the treatment of disease. Insulin's impact was so sensational because of the incredible effect it had on diabetic patients. Those who watched the first starved, sometimes comatose patients with diabetes receive insulin and return to life saw one of the genuine miracles of modern medicine. They were present at the closest approach to the resurrection of the body that our secular society can achieve, and at the discovery of what has become the elixir of life for millions of human beings around the world. So as all of you know, discoveries very rarely come out of the blue, and so what was the body of knowledge localizing insulin to the pancreas prior to 1921? The story probably can begin with Paul Langerhans in 1869, who examining the pathology of the pancreas found these islets or clusters of cells that appear to be floating in the pancreas distinct from the much more abundant exocrine or part of the pancreas, the acini, which were connected to the pancreatic duct, whereas the islets, these clusters of cells, were not connected to the pancreatic duct. Paul Langerhans did not know at the time what the purpose of these cells were or that they were actually secreting something incredibly important, and only subsequently they became known as the islets of Langerhans. So Oskar Minkowski and Joseph van Mering in 1889 and Hayden in 1893 performed very, very important experiments where they reproduced the diabetic state, they removed the pancreas from dogs, reproducing the diabetic state, and hypothesized that this was due to loss of an internal secretion of the pancreas rather than the pancreatic exocrine secretion. They performed experiments with crude pancreatic extracts, and they had some success actually in reducing the glucose and improving the well-being of diabetic animals, and actually in some cases even administered the extract to humans, but with toxicity and without success. Eugene Opie in 1901 at Johns Hopkins found a pathological connection between diabetes and damage to the islets of Langerhans, and he showed inflammation in the islets from patients who had type 1 diabetes, and many investigators actually working over the next two to three decades, the next two decades revealed the workings of what came to be known as the endocrine glands and hormones, and these studies laid the groundwork for the discovery of insulin. So here is an incomplete list of some of the investigators who played a very important role in the three decades leading up to the discovery of insulin in Toronto. I've mentioned Minkowski and Mehring and Hayden, Rennie and Fraser, Zilzer was a prolific investigator doing many experiments including trying to administer this pancreatic extract to humans, but with toxicity, Scott in the U.S., Kleiner and Meltzer, and particularly Paulescu of Romania who published his work just before Banting and Best started their work in Toronto, and he actually had success, really good success in animals. He also patented his extract and tried to develop it as a treatment for humans but did not succeed with that. And so there is this wonderful story of Fred Banting who was a general practitioner and a surgeon in a small town at the time called London, Ontario, which is about 200 kilometers west of Toronto, and he had returned from the First World War and he was trying without success actually to set up a practice and he had very few patients and was not doing well and he was preparing a lecture for medical students one evening and he came across some very interesting articles and the story is that at 2 a.m. he jotted on his hypothesis and his experimental plan which went like this, that he would ligate the pancreatic duct of dogs, keep the dogs alive until the acini degenerate leaving the islet. So the idea there was that the pancreatic enzymes in the exocrine part of the pancreas would degrade whatever this substance was that was putatively secreted from the islet and so by ligating the pancreatic duct and waiting a period of about seven weeks or so, the exocrine pancreas would degenerate and become involute and therefore it would be possible to isolate the internal secretion of the pancreas without its degradation to relieve, and he misspelled, glucosuria. So he discussed this idea with one of his colleagues in London, Ontario, who suggested that he go to Toronto, to the University of Toronto, to speak to McLeod, who was an internationally renowned carbohydrate researcher at the time and had resources and he was the head of physiology at the University of Toronto and Banting went off to speak to McLeod to tell him about his idea and ask for support in doing these experiments and the University of Toronto was actually a fantastic place for him to go to do this research, not only because of McLeod but also because it was an established medical school and there was the hospital for sick children where the kids with diabetes were being admitted as well as the Toronto General Hospital and in addition the Connaut antitoxin labs that had been established a few years earlier during the First World War to develop diphtheria antitoxin and they would play a major role in the production of insulin. So here is a picture of McLeod who was initially quite sceptical and didn't really think that Banting's idea held much promise but did give him facilities including lab space, dogs and a graduate student, Charlie Best, who began to work with him in the early part of 1920. This looks very primitive, it's a calorimeter for measuring glucose but it was actually really quite an advance and maybe a major advance for Banting and Best because it allowed them to measure glucose for example in smaller aliquots of blood much more precisely than any of their predecessors could do and it was a brutal summer, very hot, no air conditioning, lots of dogs dying, really struggling with the experiments but round about August 1920 they had some success and here you can see a graph of the decline in glucose from a dog administered this extract of a pancreas where the pancreatic duct had been ligated, they waited about seven weeks for it to atrophy, for the exocrine pancreas to atrophy and then prepared an extract and administered back into the diabetic dog and towards the end of 1920 there was a really a brilliant biochemist who was on by the name of Collum and he was on sabbatical in McLeod's lab from the University of Alberta and he was a very, very experienced biochemist and McLeod asked him to become involved in the studies towards in approximately December 1920 and so Collum made a number of changes to the protocol, first of all he started to use rabbits which was much cheaper and much faster than using dogs, so using rabbits as a biological readout of the purity of his extract, he was using the alcohol extraction method which actually had been used by others as in the first decade of the 20th century and then Banting and Best had actually also started to use alcohol and Collum had to get the conditions exactly right, the exact percentage of alcohol was just above 90 percent, the pH, the temperature and the kinds of things that a chemist would do to really optimize the extraction of a pure substance that would be free of toxic impurities, actually not a pure substance but let's say a substance that would not cause toxicity and they felt they were ready to administer this to the first human and there was this boy Leonard Thompson dying of type 1 diabetes and Banting and Best actually insisted on using their extract which wasn't quite as pure as Collum's and they administered on January 11th to Leonard Thompson with very little benefit, in fact he developed you know large sterile abscesses, very large volumes injected into each buttock and so they went back to the drawing board, Collum worked on his extraction method and just less than two weeks later came back with a much purer extract with tremendous success and in fact clinical success as well and Leonard Thompson's ketoacidosis began to resolve, he felt brighter, he felt stronger and he responded very well and that was the first successful administration of insulin to a human. So one can see that a lot of people played an important role in the discovery of insulin and I've placed Banting, Best, McLeod and Collum over here, this is 1921-1922. Very important to acknowledge all of these investigators and we won't go through their names again, there's Paul Lesko who does deserve special mention, who really did the groundwork for the experiments that were performed in Toronto. One can also question really was this the discovery of insulin, well actually not, it was really the purification of insulin to a point that it could be administered to humans as a therapeutic but really discovery came later and discovery really involves the peptide sequence, the crystallization with the three-dimensional structure, the genetic sequence, the radio-immune assay and a number of Nobel prizes going throughout the century to others who did groundbreaking work in the discovery of insulin. So one may ask was the 1921-1922 work in Toronto the true discovery of insulin and what is beyond dispute is that Banting, Best, Collum and McLeod were the first to develop an insulin preparation as an effective therapy for humans affected by diabetes and no other investigators or group can lay claim to that accomplishment. So what were the Toronto researchers' success factors compared to their predecessors who made great advances over the previous three decades? Well first of all, as we've mentioned, a large body of knowledge that had already localized an internal secretion to the pancreas. Secondly, Banting was not simply a curious researcher but he wanted to, if possible, isolate a form of internal secretion that will be of use in treating diabetes. His sheer drive, determination, perseverance and laser-like focus on developing a successful treatment for diabetes really drove this research project forward. So he was not just a curious researcher. In fact, he had almost no training in research whatsoever. I mentioned some advances in determination of blood glucose and in fact, if some of the predecessors had the same ability to measure glucose, they may have found that they had more success than they thought they did. Banting and Best worked with a very experienced researcher, McLeod, in a well-resourced research university and Collum, the experienced and brilliant biochemist who optimized the alcohol extraction method to isolate insulin relatively free of toxic impurities. And finally, as I'll mention in a few minutes, the collaboration with industry to scale up production. So this interests me a lot. A common pitfall in research is believing in one's hypothesis to the point that it impairs judgment. And so I was very interested when I read the history as to how Banting slowly came to abandon his central hypothesis that ligation of the pancreatic duct would result in degeneration of the exocrine pancreas, enabling isolation of the internal secretion. So what happened is, towards the latter part of 1920, there were delays in generating duct-ligated dogs that even when they shortened, it took at least four weeks. And McLeod wanted them to do longevity experiments. So he wanted them to administer repeated doses of insulin to dogs to show that they could keep them alive rather than single doses that would demonstrate simply a reduction in blood glucose. And so they were running out of the pancreas to make the extract. And they started to take some shortcuts and use the pancreas from only partially degenerated pancreas, but with good results. But very interestingly, they failed to recognize their own findings. And when they wrote up the findings, they claimed that the degenerated pancreas was more effective, whereas their own experimental findings really did not show that. So they were sort of blinded to what they were finding. And then Banting read a paper showing that newborn or fetal pancreas had more plentiful eyelids. And he knew, because he had grown up on a farm, that obtaining fetal pancreas from the local abattoir would be possible because farmers would often breed their cattle before slaughter. And so they started to work with fetal pancreas with good success. And finally, they resorted to using the pancreas of a non-ligated adult pancreas from a dog with a successful decline in blood glucose. So they pivoted completely from this idea that you had to ligate the pancreatic duct and, and have degeneration of the exocrine pancreas. So, so I find this very interesting because I myself, I'm sure, have fallen into this trap more than once, where I believe in my hypothesis so much that it's difficult to see to really be led by the data. And to, to see that perhaps your hypothesis was not correct. And in fact, some of the most interesting findings that I've ever derived from my research have shown the opposite of what we originally actually thought it would be. And so now the race was on to supply insulin to the world. And this was tremendous pressure. And people were dying, children were dying, and they had to start moving to large-scale insulin production. And this is where the Connaught Labs in the basement of the Medical Building of the University of Toronto started to play a role as primitive production facility. And this is an early vacuum cell. And, and actually the production started to fail in the spring of 1922. And they were really in trouble now and everybody wanted insulin. So Eli Lilly Close, who was the medical, a medical director at Lilly, became interested in the Toronto work towards the end of 1921. And he actually went to a presentation that McLeod and Banting made. And roundabout Christmas of 1921 and developed a relationship with them. And, and then developed, and then had an agreement that they would collaborate with the University of Toronto. And they would make insulin free for the first year before patenting it. And Lilly became involved and developed advances in the, of isoelectric focusing, advances in the production. And by late 22, early 23, was able to produce massive amounts of, of insulin. There was spreading excitement. You can see the press is starting to catch on to what was happening. Here's what that terrible photograph I showed you of a young girl before. And then after insulin and you see her falling out. And here the press new treatment is certain cure. Europe declares New York excited over new cure for diabetes, gives Banting all of the credit. And this was Gilchrist, one of the first adults. He was a physician, colleague of Banting and McLeod, and he was one of the first adults treated with insulin. And these wonderful, wonderful stories of resurrections in Toronto with press coverage of the first clinical trials leading to a wave of requests for this diabetes cure. And, and some of them, and, you know, well, well-known, for example, Elizabeth Hughes, the daughter of the secretary of the Secretary of State of the United States. Wonderful young woman. And there's a whole book written about Elizabeth Hughes. And, and she was one of Banting's original patients. And she lived for many years. And James Havens, etc. And these beautiful, for example, letters to Fred Banting, to the doctor who cures diabetes. And about getting her, getting brave enough to give herself her own injections. And, and so sorry, more of that, but I'll skip over the slide. And making insulin at a low price was very important. And actually, I don't know if you can see this table in the middle here, but the price fell progressively up till about 1944 and then slowly began to rise. I'll touch on this a little bit later. But it was very important to make this insulin available for everybody, regardless of their financial status. So why did the discoveries of insulin not attempt to profit personally from the discovery? Well, they sold their rights to the University of Toronto for a dollar apiece. And the university then filed an application for a patent. And they felt that providing their patent to the university would prevent the discovery from being commercially exploited by a single company. So creating a patent was actually a very controversial thing for the University of Toronto. And they really had to defend what they were doing. And they felt that their justification for filing a patent was when the details of the method of preparation are published, anyone would be free to prepare, prepare the extract, but no one could secure a profitable monopoly. So that was why they actually patented insulin. But the discoveries, discoverers and the university were very reluctant to be associated with patenting on ethical grounds that commercialization might make the discovery unavailable on a worldwide, widespread basis. And Banting famously declared that insulin does not belong to me. It belongs to the world. They had very high ethical concern that ensured that even the most financially destitute of patients would not be deprived of insulin by commercial forces. And the discovery of insulin provided a formative test case for the relationship between academia and industry. Unlike today, in which commercialization of medical discoveries is a point of pride for researchers and universities. In 1921-22, researchers and universities felt uneasy about profiting from medical discoveries, which were first and foremost to benefit humanity. And 100 years after its discovery, insulin is still widely unavailable to millions of people in need. Globally, one in two people needing insulin lack access. Improving insulin availability and affordability is very complicated and needs to be addressed through national and global actions, including prioritizing the supply of more affordable human insulin, increasing competition through the use of lower priced quality-assured biosimilars, negotiating lower prices from manufacturers, and improving distribution systems. And the WHO Global Report on Diabetes states that people with diabetes who depend on lifesaving insulin pay the ultimate price when access to insulin is lacking. So this was one of the shortest times between discovery and awarding of the Nobel Prize. It was about 18 months. And if you notice this, but the prize was given to Banting and MacLeod, not to what most people think is Banting and Best. To Banting and MacLeod. By this time, Banting and MacLeod had a fairly toxic relationship. It's very complicated. And I didn't go into that. But Michael Bliss deals with it very beautifully in his book, The Discovery of Insulin. But Banting was furious at this, and he immediately split his prize with Best. MacLeod then split his prize with Colep. And in the end, I think, you know, the fact that all four of them received some acknowledgement is really correct, because all four were critically important for the discovery of insulin. So advances in insulin and diabetes treatment over the past 100 years have been amazing. Insulins have been purified and more concentrated. Modified insulins, having delayed absorption from subcutaneous depot to provide longer duration of action. Advances in glucose self-monitoring, including capillary glucose testing. Discovery of the hemoglobin A1C to monitor glucose diabetes control. Improved insulin devices, delivery devices, pens, and fusion pumps. Manufacture of the first human insulin by Lilly in 1982. Ultra rapid, ultra long acting insulins, continuous glucose monitoring. Insulins that now target the liver and also will switch down their effectiveness during hypoglycemia. So there are ongoing tremendous advances. And of course, many advances in the prevention and treatment of diabetic complications. For type 1 diabetes, the Holy Grail still remains physiologic insulin replacement. So we've got continuous glucose monitoring now. That was a very tough engineering hurdle to surmount. There are insulin and fusion pumps. There are algorithms that link the two. We're very, very close to having closed. I mean, we basically have closed loop systems. But of course, this takes billions of dollars for regulatory approval. There is a very, as you know, do it yourself, very active community of people on the internet who can jerry rig these things and create and set up closed loop automatic or mechanical devices. And also the many advances now in cell-based therapy. And so I thank you for your attention. This actually the presentation is sort of a very brief synopsis of an article I wrote with my colleague Pat Brubaker that was published in the JCI in January this year. So thanks very much for your attention. Thank you, Dr. Lewis, for a really fascinating presentation. I think also thank you for reminding us that discoveries are made on the basis of many people's work, not just the few that sometimes get the most recognition. I would also encourage everyone who listened to actually look at that article on JCI. It's really very, very, very well done. I truly encourage you to get a copy and look and read at that. Please put your questions into the Q&A section as we're waiting for people to actually submit questions. Let me begin with a few questions assuming the moderator's prerogative. There is a very often quoted 2018 study in the British Medical Journal Global Health where the authors spent some time looking at what it costs to actually produce insulin. And then they based that cost on a 40 unit per day use over the course of a year and basically came out. And these are US dollars, so obviously not applicable, unfortunately, across the whole world. But for human insulin, somewhere in the range of $50 to $70 per patient. For analog insulin, somewhere in the range of $80 to $130 per patient, that's per year's use. Certainly here in the US, and I recognize that we have many different participants from different countries participating, the cost of insulin is quite exorbitant. And that certainly is one of the limits to access to insulin. Where do you see changes could be made to make insulin much more accessible, much more affordable? Whatever it is that can allow easier access to the individual needing insulin. Well, thank you very much, Dr. Trentz, for first of all, your very kind comments and then also for that question. Let me say that I am not an expert in the pricing of insulin and the issues surrounding the unaffordability of insulin. So I'm really not an expert. I'm particularly not an expert on the situation in the United States. But I have a few comments. One is that it is a huge worldwide issue. And I believe the issue is different in different countries. Let me just tell you that even in Canada, where we have a public health system, we do not have universal pharmacare for everybody. There is drug coverage for people over the age of 65. And in certain provinces, such as Ontario, where I live, there is also drug coverage for people under the age of 25. And then, of course, if you meet certain criteria for very low earnings, there are other programs that can kick in for people between 25 and 65. But there's always the problem of the working poor. And I know that that's a problem in every country. So believe it or not, we've even seen people in Canada, for example, a student having to ration their insulin with type 1 diabetes. So it's a worldwide problem. The WHO is taking this very seriously. We had a public celebration, we being the University of Toronto, had a public celebration for the discovery of insulin just last month on April 14. And the WHO piggybacked a session during the day where they had a lot of very influential people. And they specifically discussed this. And I believe they'll be coming out, if not already, they'll be coming out with a report on it. It is something that needs global attention. There are issues. For example, I mean, just one of the issues is that insulins, it has been very difficult to produce a biosimilar insulin. So if there's something like Sanofi, I think, has something like 50 or 60 patents on their Lantus insulin. And very ready to challenge legally any group that was trying to create a biosimilar insulin. So that would just be, for example, one issue. But there are many, many issues regarding affordability of insulin. And it is something that I think an organization such as the WHO really needs to address. I believe that the pharmaceutical companies are very open to dialogue and participating in this. So I don't think we should just see them as the bad guys. This is not true. But they have to be part of a solution. And I think that they're ready. And I think that dialogue is really beginning to happen. It's good to hear that there is some momentum. We do have a question about fish insulin. And whether you see that as potentially an area to explore more. It's available very early on in the insulin story, but has kind of fallen off the wagon, so to speak. Yeah, so you said fish insulin, correct? Yeah. Very interestingly, for those of you who are not familiar with this story, the early discoveries of insulin, McLeod, for example, really devoted a lot of his career to that after this initial purification of insulin. And unfortunately, it didn't really go anywhere. I'm sorry. I'm not an expert on this. I'm not sure why that would be helpful, because now we actually have human insulin that can be produced in unlimited quantity. So we're no longer dependent on extracting insulin from organs. Traditionally, it was beef and pork insulin. And so I don't believe that that is a supply issue. And nor would one really want to give an insulin that the peptide sequence is different from that of humans. So I may be a little ignorant on this, and perhaps there's something I don't already know. But I can't really think why that would be a tremendous advance at this stage. I'd like to actually talk a little bit more about the future of insulin. Obviously, we've gone from basically regular human insulin, so to speak, animal insulin, rather, to human insulin, to analog insulin. What do you see as the future of insulin? We now have proposed once-weekly insulin. That looks actually rather good. We're also seeing some very early studies looking at glucokinase receptor oral pills to enhance the effect of insulin. What are your thoughts if you could have a crystal ball into the future? Again, I sort of start the answer to this with an apology, in that I have my views, and I may not be the most popular person with the pharmaceutical industry. But OK, so I take care predominantly, I take care of type 2 diabetes, 90%. And really, with type 2 diabetes, one needs what I would call bulk insulin. Because patients have both endogenous insulin secretion and insulin resistance, it actually is easy peasy to manage diabetes with insulin because of both those problems. So for example, we almost never use multiple daily injections of insulin, and one doesn't need the kind of precision diabetes management. So a lot of the time, you can use a premixed insulin, et cetera. And so I think that these types of advances have small incremental benefits. It's to be seen, whether a once a week will enhance adherence. I might have some patients that that might be helpful for. I'm not sure. I get concerned about insulin that cannot be removed, floating around for a week. And things change with people and hypoglycemia. I mean, I have had some problems with the 48-hour insulins in my elderly patients. So I think for type 2 diabetes, these will possibly be small incremental advances. Now for type 1 diabetes, different story. And I personally don't actually manage type 1 diabetes. In my institution, we have experts on insulin pumps, et cetera. So we have a major problem in that we do not currently have physiologic insulin replacement. We recently wrote a review in Cell Metabolism on portal versus systemic. So we give insulin through the wrong route, right? And that's a problem. You know, a pancreas is this mini-computer checking not just glucose, but other metabolites at the same, and secreting into the right place, into the portal vein, second by second. So major, major problems. I think that some of these insulins are tremendous advances. I mean, for example, and actually, to be fair, even in type 2 diabetes, going from NPH to, for example, Lantus, and the other long-acting insulins, was a tremendous advance for us. And so certainly, and the ultra-short-acting insulins are a tremendous advance for type 1 diabetes, but ultimately, okay, the stopgap will be mechanical devices that are getting better and better, and closed loops that are very important, ultimately cell-based therapies. So I think that these are going to be tremendous and very helpful for people who have zero insulin secretion and are insulin-sensitive. And so insulins that will turn off their activity as the glucose drops are going to be important. I think that these are all going to be very helpful, but I think what's ultimately going to be the game-changer will be closed-loop mechanical devices, and then ultimately cell-based therapies. Clearly, as technology moves forward, there is a cost associated with that also, totally independent of the insulin that these devices may contain. You mentioned that it was felt to be a step forward moving away from NPH and regular insulin. Do you see any role for those insulins? Because as an example, in the U.S., you do not need a prescription for a vial of NPH or a vial of regular, and they are very, very cheap, relatively speaking, at about $30 in certain pharmacies. Is there a use? Can they be used? Should they be used? Well, as much of an old country doctor as I am, I don't believe that would be optimal therapy at all for someone with type 1 diabetes, okay? At the very least, at the very least, we're talking about multiple daily injections of insulin with adjustment according to carbohydrate counting, and certainly the short-acting, ultra-short-acting insulins are extremely helpful, and the ultra-long-acting insulins. We don't treat people with type 1 diabetes with NPH and regular insulin, and I don't think that is appropriate. Type 2 diabetes, many of our patients are older, and a lot of my colleagues very easily put these patients on multiple daily injections of insulin. I think if we really monitored, we'd find that they're not taking it three times a day. They're certainly not adjusting it. Maybe they're taking five units, five units, five units, they're not adjusting, they're not monitoring, et cetera. It is an enormous burden on an elderly person, okay? Someone in their 80s taking multiple daily injections, so simplicity is very important. I personally have a lot of use for type 2 diabetes, and I'm talking about hyper-insulinemic or insulin-replete, insulin-resistant individuals. I personally have a lot of use for pre-mixed insulins. I have been accused of that being dinosaur medicine, but it works beautifully, and the efficiencies are 6.5% without hypoglycemia. I think that simplicity for type 2 diabetes is very, very important, but of course, there is a huge range of phenotypes with type 2 diabetes. There are people who are more insulin-deficient and insulin-sensitive, and they do not do well with these more simple regimens, and those are the people who are progressing to multiple daily injections of insulin, but type 2, and also with many of the new therapies, we're putting fewer people on insulin these days, so depending on affordability and whether people have insurance, et cetera, what age, we're much quicker to be using the GLP-1 receptor agonists and SGLT2 inhibitors, so I'm personally putting far fewer people on insulin these days, but I think, obviously, type 2 is quite heterogeneous, and there's no single size that fits all, but simplicity, particularly in older people and disabled people, is very important, and so I'm not sure if an ultra, ultra-fast insulin is going to make any difference whatsoever to someone like that who is insulin-replete and insulin-resistant. You touched a little bit on hypoglycemia, which obviously we all know is a significant barrier to, oftentimes, the regimens that we would like to have our patients on. Are you using a fair amount of continuous glucose monitors in your patients with type 2? Type 1? Where do you see that as a complement to the use of insulin, or actually as a complement to the other therapies that we use with diabetes, exercise, food choices, food and milk choices? Yeah, so I'm always very careful not to promote any product. It's always easier for me when there's, at the present time, a single product that really takes this to another level, and fortunately, I don't have any conflict of interest. I'm not on advisory boards or anything like that, but the Freestyle Libra glucose meter as a prototype, and I understand that there are more companies coming out with similar products, but that was truly a game-changer in terms of its affordability, and it's still expensive, by the way. Our patients, at $200 Canadian a month, including tax, can't afford it unless they have some insurance or people over 65 on insulin. They do get it covered, but that has been a game-changer over the finger sticks, and gives us insight into the patient's glycemic control over a 24-hour period that we never had before. At present, because of payment, reimbursement, we're pretty limiting. It's limited to those on insulin, but that is enormously helpful. When our patients have that, and they can connect it to our website, and you're seeing right inside the body. The other thing about it that's very interesting is our diabetes educator nurses for years have said, well, glucose monitoring is a tool to enhance lifestyle adherence and assist people with lifestyle, and actually, the data never showed that. In fact, if anything, it's sort of a disincentive, but the continuous glucose, the flash glucose monitoring with something like the Libra has, I believe, provided a tool that does and can be used for adjustment of lifestyle, what people eat and how they exercise, because they actually, for the first time, really see the changes. I think that that's very interesting. Obviously, for type 1 diabetes with the bells and whistles and the accuracy and the alarms and things like that, the true CGM is extremely useful, and particularly in situations like pregnancy, et cetera. Of course, based on affordability, that's state of the art and has absolutely changed things. That was a very difficult engineering problem for years and years, but that's been solved. Now, closing the loop with pumps, et cetera, we've got it already. Within five years, it's going to be readily available, but there is a do-it-yourself group on the internet that already is hooking up closed loop systems. I think that, again, I don't even get my patients to monitor their glucose if they're on anything other than sulfonylurea or insulin. I personally rely on the four to six monthly fasting glucose and hemoglobin A1C to make the adjustments of the SGLT2 inhibitors, metformin, GLP-1 receptor, agonists, and DPP-4 inhibitors. I don't get my patients to spend the money and do that because I don't need it. I can make the adjustments based on those two readings, fasting glucose and A1C, every four to six months, depending on stability. I am acknowledging now that at least the flash glucose monitoring, if they can afford it, is a tool to help adjust lifestyle. It's absolutely essential for type 1 diabetes or what I would call type 2 diabetes that is insulin deficient, insulin sensitive, and there are a lot of those patients around. There are the leaner patients with type 2 diabetes who have wider fluctuations of glucose. Let me circle back a little to your comment about your use of the pre-mixed insulins. There's also obviously pre-mixed long-acting insulin of various natures with a GLP-1 receptor agonist combination. Do you use that in your type 2 population? I haven't personally used that. I always, again, I'm very old and I'm a bit of a stick in the mud when it comes to certain things. Don't take me as the great example. I have resistance to certain things, but I've always had problems with very different medications being combined, for example, a statin and a calcium channel blocker. Once the patient's on those, and then for cost and ease, I don't mind switching to those combos, but I find it hard to adjust them independently. I would say that if a patient's already on a GLP-1 receptor agonist and on insulin, that seems like a really good combo to move to for ease of administration and cost, but I'm kind of reluctant, and that may just be me, to adjust things like that independently. To be honest, I'm not even sure if those are approved yet in Canada, but I have not had any use for those types of combination therapies. My use for, again, just to make this clear, for things like 30-70 or a premix insulin with a short-acting analog, the reason is because in those patients, you don't need precision insulin adjustment. You need what I call bulk insulin. You just don't need the precision, and the A1C is easy-peasy to control, so I don't have a problem, but I'd never use that in someone insulin-deficient, insulin-sensitive. Cannot do that. So one question, and it's a little bit speculative, and I apologize, but we have been very kidney-centric, heart-centric in our diabetes population, particularly the type 2 population, and I have to say type 1 somewhat, to the point that if we think about what insulin did in your wonderful presentation, it provided longevity. People survived. They lived, and as we all live longer, we see more of the other kinds of issues and concerns such as cancer, other kinds of chronic conditions. Have we become too heart-centric? Have we become too kidney-centric to the exclusion of being as vigilant with making sure that our patients have their mammograms, their colonoscopies, all the other things that normally one would consider part of health maintenance? Well, the first response is I hope that that's not the case, and so I am a specialist in endocrinology and diabetes, so I'm not the one ordering cancer screening, et cetera, and I certainly hope that that's occurring by the patient's primary care physician, and I just personally don't do that, but that would be a terrible tragedy if these proven screening methodologies fell by the wayside, but as a specialist, I think we're in a new era. It's just really interesting and very exciting, so with the SGLT2 inhibitors and the GLP-1 receptor agonists, which have cardiorenal benefits and weight loss benefits, it's something new, so up until these two classes, essentially, it was a matter of lowering glucose below the threshold for microvascular complications and doing it safely and without side effects, okay, so metformin, DPP-4 inhibitors, insulin, et cetera, getting that fasting glucose below 7 millimoles per liter. I'm sorry, I understand many people are thinking in milligrams per deciliter, but below 7 millimoles per liter and or A1C below 6.5% puts those levels of glycemia below the threshold where there is a strong inflection in the curve that increases risk of microvascular complications, but there were no other benefits, only side effects like, you know, possibly hypoglycemia, et cetera, and no proven cardiovascular benefits, so for cardiovascular, it's blood pressure and ACE inhibitors and statins, et cetera. Now, with the two new classes of therapy, we are now aiming to reduce glycemic thresholds below the microvascular risk threshold with added benefits of weight loss and cardiorenal benefits, and so these medications and cost is a major issue, and there are some side effects, okay, that should not be ignored, and for example, SGLT2 inhibitor is not quite as easy to use as a DPP-4 inhibitor, for sure not, but still very safe, so now we've got these added benefits, and it actually raises some very important questions as, you know, at what level of glucose should we be beginning these, be starting these agents, and we haven't really answered that yet, but we do know our cardiology and nephrology colleagues are starting to use these, and with evidence in non-diabetic individuals, but insulin itself is not a good drug, okay, it's a necessary drug, but it's got lots of issues, not least amongst which are hypoglycemia, okay, and it's just, it's something we hate to use but have to use if we have to use it, we've got to get those glycemic thresholds below the microvascular complications. It is not acceptable to avoid insulin and leave the patient running sweet, okay, so I'm sorry, I think I've gone totally off and not answered your question, and I actually at this stage didn't really remember your question, and that sometimes happens. No, you actually did answer it, so thank you, yes, you did, but let me just ask you to comment also on, as you just said, insulin for many people is necessary, it's just necessary because it's effective. How comfortable do you feel adding to insulin than an SGLT2, or a GLP, recognizing that you just said that you don't do this very often, but is there comfort there? Yeah, very comfortable, so ideally we would go in the other direction, right, we would start those drugs prior to initiating insulin because they're available these days, and I have tremendous comfort using these classes of agents before insulin. Having said that, I think we need to have a lot of respect in elderly patients for SGLT2 inhibitors, okay, so lots of respect, so when you're using it in a 75 plus year old and or a frail person, with big caution, okay, and I'm still reluctant to add those drugs if the A1c is sitting at six and a half percent before putative, you know, cardiorenal benefits, and usually, you know, often weight is not an issue in the really elderly, okay, so, you know, I am being pushed by nephrology colleagues, by, you know, there's an industry push, and we have to do the right thing, but sometimes you can get into big trouble with SGLT2 inhibitors in older patients, and I don't just mean the DKA, you know, the euglycemic DKA, that's very rare, but, you know, extreme polyuria is something that can occur, we've all seen it, and deterioration of renal function, etc., so just with caution, but very good drugs, okay, and GOP1 receptor agonists, you know, big issues here is affordability, and who, you know, etc., but very comfortable. Now, in those who are already on insulin, we're talking about your obese insulin resistant person with type 2 diabetes on a fair slug of insulin, I think there are real advantages to adding these drugs, one, maybe both, to reduce the body weight, to realize the cardiorenal benefits, and to reduce the insulin dose, okay, whether you can get them off insulin 100% is probably unlikely in some of these patients, but yeah, no, we do that quite a lot, actually, we sort of retrofit patients who never had a chance to get on those drugs because of the many benefits, absolutely. Well, we're rapidly coming to the end of the hour, this has been just delightful, I thank you so very much, Dr. Lewis, for a very informative presentation and a lively Q&A, I hope that everyone's questions have been answered, and I look forward to hearing more about insulin as the program continues. Thank you again. Well, thank you so much, I'm really appreciative to the organizers, and I have named lectureship, and I'm so appreciative for that, and thank you for inviting me, and it's been a great pleasure meeting you, Dr. Trentz, and thanks to everybody, have a good meeting. Thank you. Bye-bye.

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