Of Zebrafish and Diabetes - Healthcare Triage Podcast

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Hi, welcome back to the healthcare podcast. This podcast is sponsored by Indiana University school of medicine whose mission is to advance health in the state of Indiana beyond by promoting innovation and excellence in education research patient care is school medicine is leading Indiana university's first grand challenge. The precision health initiative with bold goals to cure, multiple myeloma, triple negative, breast cancer and childhoods coma and prevent type two diabetes and Alzheimer's disease. And today, we're gonna be talking about type two diabetes diabetes in general. Our guest today is Ragu MIR Mira professor of pediatrics and medicine at Indiana University school medicine, I'm gonna let him introduce himself. Thank you very much, Aaron I'm the ally. Lily professor in pediatric diabetes in the departments of pediatrics and medicine is school medicine. Fantastic. I wanna start basic could you just tell everyone. What is diabetes. Yes. Diabetes. I think most people understand diabetes. Being a disorder of high blood sugar, and it's affectively when your body is unable to utilize the nutrients that you take in and your blood sugars go up because your cells can't take up those nutrients particularly glucose, and and it's typically when you don't have enough insulin circulating or the insulin. That is circulating doesn't act. Very well. So what is insulin do so insulin causes yourselves, particularly your muscle and fat cells to take up nutrients, especially glucose, which is one of the fundamental nutrients. Okay. And so why do we need glucose so glucose is used primarily to create all of the components that are important in the cell. So they're used as fuel storage. They're used to create protein. It's used to create fat. So glucose is really a fundamental component of our nutrition and all living cells use it so annoyed. Normal functioning body that has no issues. I soon we eat food the body absorbs glucose from that food. What happens then so it it enters the bloodstream through the gut, and then the first organ that sees it one of the first organs that see it as the patriots. And when the pancreas senses the glucose that's present in what you eat it releases insulin along with that glucose, and then the insulin does what and then the insulin then travels throughout the body to different cells. And then it binds to those cells literally interacts with the cells, and then it causes those cells to send a signal that allows them to take off the glucose, so the glucose Romley go from the bloodstream into the cell. But if there's no insulin it just winds up sitting in the bloodstream crack, and that's why get super hot. That's right. And then the only way you get rid of it is through your P. And that's the reason why people with diabetes have such high blood sugar in their urine. So. Is the high blood sugar bad? Well, it's bad. Because as I said, the cells need the glucose to produce the nutrients, like the proteins and the storage form of energy. When can't do that your body, literally starves. So even though there's plenty of even though there's plenty of sugar circulating around your body starves because it can't take that sugar. Okay. So why would people not have enough insulin? Well, there several reasons for that. The first reason is that you could have an autoimmune disease that destroys the cells that produce insulin. That's what we typically call type one diabetes, but there are other forms of diabetes typified by type two diabetes in which your body does produce the insulin. But it doesn't produce enough. So that the cells don't really see enough insulin and take it up. So why I mean is it just an autoimmune disease or is it that they get that from? Earth. They get an infection. What causes the body to go after the that's a that's a very interesting question. And that's one of the hot areas of research today is why why does this happen and who does it happen in? And when does it happen? One thing we know is that typically happens to most people not in their infancy, but typically after one or two years of age, so that means that you're born without that problem, and then it develops over time. So we think that something in the environment must trigger that process. So that's one thing. Another thing that we know triggers the process of not producing enough insulin is what you eat. So if you eat very high fat diets, and you get obese you have a problem utilizing that insulin. I wanna stick the type one diabetes for a few more minutes, which type two so is it genetic is doesn't run in families. So it is genetic. We know that there are certain genes that are associated with it. But even having the jeans isn't enough. So we know that it does run in families. But it skips sometimes many generations. And sometimes you don't see it in brothers and sisters. So we know that you have genetic risk. But then beyond that genetic risk. You have to have some kind of environmental exposure could be virus. It could be something that we eat. We don't really know. Maybe something that we don't eat. So whatever it is that combination of the genetics and the environment, you know, just triggers this process and certain individuals. So does is it ever stop? Or once it starts killing off the tanker, sells it eventually kills them. All that's the thinking in general is that once the process starts. It's very hard to stop it. We've tried a variety of different drugs that have been in clinical trials to try to stop the process. They seem to slow it down. But in general, the process proceeds no matter what we do. How do we treat that? I know that just of it is give insulin. Clearly, but but is that the mainstay I mean is that just all we can do for type type one diabetes. The only real drug. We have right now is insulin. So how are things change stay in thirty or forty years because clearly we've been using insulin for a long time. So the things that have changed the kinds of insulin that we use. Now, we have an ability to find tune how quickly the insulin ax. We have the ability to also fine-tune how we deliver it. So typically, we used to do it by just syringe bottle drop insulin injected, but now we have a variety of different pumps that can inject it continuously. And even were moving to the point where there's very little sort of involvement of the individual himself or herself. Because now we have pumps that are connected to sensors and that they can use these fancy algorithms to determine how much insulin to give and win do people still need to correct for what? They're eating or is it gotten so good that now just runs on autopilot. No, you mean the pump systems. No, we're not that good yet. I think that's alternately where we're trying to go with a lot of that technology. We still have to do a lot of monitoring. We have to be careful what we and how much of the carbohydrates or fat that we eat. And and when we so all of these are still variables. So we're not quite at that. Stay not. I mean, it just seems to me that that we should be able to. I mean, if the pancreas is working by detecting insulin, and then releasing insulin in detecting glucose, excuse me. And then releasing insulin response to it. Why can't we set up monitors that detect glucose in the blood, and then just administer the amount of insulin for it? So we have those kinds of systems than reasons they're not as perfect as we'd like, partly is the technology. But the other part is the physiology because insulin goes right into the bloodstream, but when we injected it goes. Under the skin, and it takes time to reach the bloodstream the same thing with the sensors that we have for glucose is ideally, we'd like a sensor sitting right in the bloodstream where we can detect how much glucose levels are. But they're actually sitting underneath the skin. So it has to defuse, and then we have to use mathematical algorithms to figure out if the blood if the glucose in that skin is so much how much does that mean it is in the bloodstream so these are complex, and you can imagine it varies from individual individual shore. Is there any work towards I know artificial pancreas putting actually in there that would detect and then release inside the bloodshed. There definitely is as you can imagine any of those types of devices are more invasive, they're prone to infections and so forth. But you know, when we had these large devices that that that can actually be sitting inside of, you know, the bloodstream detecting everything, we know we can control things much much better. So. Where where's the sort of research going for? I don't want to type one diabetes. Where's the research going and type one diabetes? I mean is it just to refining the way that we deliver and technology. Let's call it. How how can we better deliver and sense glucose and and deliver insulin? So another area that people are getting very excited about is creating new cells that produce insulin. And there's a couple of ways to do it. So one way is to trigger the body to produce new cells. We know that these cells exist, we know that you're born with them. But then the immune system kills them off. Why can't they grow back? So part of the research in particular research. My live is doing is trying to figure out how come we cause these cells to grow again? And then if they grow again, then then the other question is how can we get them to evade the immune system? So those are things that we're working on. Another approach is a transplantation. So we can take cells from your skin convert them into insulin producing cells, we can give those house right back to you without immune suppression. And they could produce a lot of insulin. So we can do that. We just haven't gotten to the point where we can produce a pure population of insulin producing cells that the FDA says a safe enough to give back to you. But that would seem to be cured. If if you could I think either of those that I had just mentioned growing your own cells in their native pancreas or being able to produce new cells from your skin would be curative out to think we're close to that. Well, I think that we have challenges. So for example, if you can cause your cells to grow again, or cause those cells from your skin to become insulin producing cells. How can we ensure that they won't become cancerous? Right. Right. So that's a big concern because causing things to grow. So we're worried about that in animal models. When we do this. They certainly cure diabetes. But then, you know, long-term animals don't live very long humans level lot longer. So how can we ensure that we don't cause cancers or tumors? So I think that that is going to be one of the biggest hurdles to ensuring that it's safe enough for delivery into him. And so we have the technology the biologic technology to do this. The the challenge is our safety. How do we get there? Like, what do we need to do to ensure that need long-term trials or is it? No, it's not going to be long term trials because even trials we have to make sure that it safe in worse. Right. So it's going to actually be more technology. So if we can cause a sow to grow how can we control it? So can we cause that cell to stop growing when we want it to stop growing? And so now, there's a lot of using gene editing technologies that people have heard about and other sort of fancy. Molecular tools are able to try to control. Oh, that tempo of growth of these cells. And then literally be using genetic switches to turn these cells off when we want them to. So that's where some of that technology from the molecular side is going. It's fascinating help out. Is there any working towards if we can catch people before the entire pancreas has gone to stop the stop the destruction of final sells? That's another area where the school of medicine school of medicine is focusing a lot of its efforts. First thing we need to do is identify who's going to develop diabetes because the risk of developing diabetes is pretty small it's less than one percent in anybody. And even if you're high risk meaning that you have the genetic risk. It's still maybe two to three percent in your lifetime. That's not a lot. But it's enough that you'd say jeez. I wish I had a simple blood test. That can tell me I'm going to get diabetes or not. So part of what we're working on. Now is denting blood test because we're gonna dentist by a blood test. That says, hey, your likelihood of getting diabetes in the next five years is very high. Then we could potentially than us medications that can turn off the immune system or temp at down to prevent that from happening, which of these avenues we've talked about. You think is the most promising is is that the replacement cells. I think they're all promising. I think that's part of the reason why there's so much effort put into all these areas in prevention in technologies and then in cell replacement, and so there many funders of this type of research, the national institutes of how eighty are f the ADA a lot of private organizations are putting money into this. So, but they're doing it in a way where they're saying. We're not putting all our eggs in one basket. And I'm also struck by it seems some of them are. Men are geared towards how do we find a good way for you to live with this versus curative, which is completely different? I mean that would just be amazing. Well, I think curative is you know, the long term goal, but managing diabetes is the short term chore. How do we keep people with very brittle? Diabetes blood sugars, go up, they go down one of the biggest risks in diabetes. I mean, certainly there complications we talk about him kidney disease, I disease, but the real big risks are low blood sugars because they can kill people very quickly. You're driving your blood sugar goes low you get into an accident, for example, or your slightly older. You're an elderly person you have a low blood sugar having a heart attack. So so what we're trying to do with a lot of the work. That's literally hitting you know, people today is how can we manage the blood sugars better keep these ups and downs? How can we predict low blood sugars? How can we prevent low blood sugars are there better insulin's that can prevent that. So that's really the direction that we're going in right now that can affect somebody year from now, whereas the cell replacement probably looking realistically ten fifteen twenty years. So most people diagnosed with type one diabetes when their children. So that's what we used to think. And we used to call it a disease of childhood. But I think what we are learning. Now is that type one diabetes is a spectrum of diseases. It it becomes most obvious and children, but adults get it too. And we often misdiagnosed them as having type two diabetes. And then what we learn over time is that they actually slowly behave more like type one. And so what we're learning is that depending on the age in which you get it the severity of the onus the the repeatedly of onset of the onus varies so older. People might have the disease and not recognized. It's type one diabetes are like to shift gears. What's what is type two diabetes, and how is it different than type one so type two diabetes. I think most people associate type two diabetes with obesity. Uh-huh. Right. It's not exactly completely true. But it's true for the majority of people and what we know. Now is that when you get overweight and obese your cells for reasons that were still figuring out don't seem to respond to the as well to the insulin that you have. In other words, your body needs to produce more insulin to get the same effect. It would get if you were lean. So it's not as much problem with the pancreas cells to produce insulin as all the rest of the cells that are necessary to absorb it. So a little of both because it turns out that you can imagine if you can climb up a hill the higher that hill the slow harder it becomes to climb because you poop out, right? So if. The pancreas is trying to produce a lot of insulin because the cells don't respond to it as well. Eventually it poops out. So if we had a really powerful pancreas that can produce as much insulin as we need despite how how much the body needs. Then you wouldn't have a problem. So why do we associate it with obesity? What why is it wisn even matter? So it matters because the majority of people that have type two are obese. Okay. But there are people who are thin that can also have it because they have other reasons for this resistance to insulin. What we should call it. But it is also the case that people with type one diabetes can be obese is well, and for that reason sometimes we miss associate that disease as being type two. So so the the reality is that as the population is getting more obese the the prevalence of diabetes is getting greater and so we. We know that what you eat. How much you eat, and how much you weigh have a direct impact on how whether you are going to get diabetes or your risk of diabetes. So how do we treat type two diabetes? And how's that different than I want alternately, you can treat type two diabetes the same as you treat type one. So you can give insulin. But because as I said your pancreas still produces insulin. There other drugs that we have that can help your pancreas. So we have drugs that can cause your pancreas to produce more insulin. We have drugs that can actually cause your body to respond to the insulin better. And then you know in any kind of lifestyle changes you can make to reduce weight can help as well. So things that those things you can't do with type on why does reducing weight help? So what we know is that when you reduce your weight, your cells become more sensitive to the amount of insulin that you're already producing. So the amount of insulin that you're making. Ng then acts better. Why is that what we know is that as you get more obese your cells when they see insulin. They have to you know, what we call in the molecular field transducers that signal what that means is it has to see the insulin. And then has to convert that insulin in a way that can allow that cell to take up the glucose, right? So it turns out that at that molecular level when you get obese for reasons that are unclear still that ability to transducer that signal that ability to see that same amount of insulin and caused that cell to respond in the same way is impaired. So people can lose weight can they cure their type two diabetes. So many people who lose enough weight can and fact be free of insulin free of any medications to control their diabetes. Do we say their diabetes is cured? I I would say it's hard to say. Say that they are cured sort of once you have the disease you have the disease, which means that you're always at risk forgetting it again. So I what I usually say to my patients is that. I encourage them to lose weight because then they don't have to take all these medications, but they have to keep that way down or the diabetes will come back. What are the other types of medications besides insulin that we would use? Yeah. So there are other injectable medications. They're not insulin. But their medications that you can inject in that literally caused the pancreas to produce more insulin. Some of those medications also cause you to eat less. So you lose weight, so those classes of medications called GOP one receptor agonists, so that's one class and it's an injectable medicine. So is that a one day injection or is that every time you eat type of injection? So that is either a once a day or once a week. So you don't have to inject that every time you eat. So that's actu-. Early. A reason why that drug is very popular in it gets used quite a bit. So it is a popular medication. But again, people sometimes require additional medications beyond that when that doesn't work, and what are other types of Medicare. So there are pills that we can take for it. So we've got pills that can cause your pancreas to produce more insulin. Those pills have been around for decades. We know they work, but the problem with those pills, they're called self Anneli, they caused people to gain weight, and that's not as attractive as some of the other pills that we have now. So we have another pill. That's also been around for decades. Many people know it it's called metformin. It's a tried and true medication. It's relatively inexpensive. And in fact, it we call that either a weight neutral or slightly wait negative drugs. So it could cause some people to lose weight. It doesn't stimulate the pancreas to produce more insulin. But it causes your cells to respond to the insulin better. It's very good medication, and it's well, tolerated by most people, and then we have other pills that do similar things, but maybe not in the same manner. So we have medications called DP four inhibitors drugs that inhibit an enzyme and that cause your body to respond a little bit better to insulin. We have another class of medication called SGLT two inhibitors and what they do is. They basically cause your kidneys to just get rid of the excess blood sugar. So your blood sugar's fall, but largely because your kidneys are getting rid of more of it each of these medications works, they lower your blood sugars and in large part, they can protect you even from getting heart disease and some of the other complications of diabetes, but they each have side effect profiles that work well for some people and not well for others. How do you decide which to use? So I think that there are many ways people go through algorithm. So to speak what we like to do in our clinic is personalized therapies, so we like to ask the very simple question. You know, what are the features of any given individual. Maybe there are psychosocial features. You know, there's things that some people are afraid to use needles. Some people, you know, like taking pills once Dave versus three times a day. So one of the things we liked to do is personalized therapy as much as we can we like to go with inexpensive therapies or some people that don't have, you know, a lot of disposable income that they can put in medications, and they're very tried and true drugs that that that are very inexpensive. We tend to like to start with pills, okay for type two diabetes and we'd like to start typically with metformin because it's it's cheap. It's easy to take you have to take just twice a day. So that's. Good pill to start with. And I think for the most part we like to start almost everybody we can on that pill, and then where we go after that. I think is you know, on a case by case basis. I think we'd like to keep people away from insulin for as long as we can because many of these medications are as I said can cause you to lose weight insulin by the time you get on insulin. Most people start gaining weight on that medication. So we like to avoid it. If we can someone with type one diabetes constantly monitoring their blood sugar adjusting, their insulin is the same kind of mechanism and type two you have to keep checking your blood sugars or more, you take the pill, and you just hope for the people are on pills. We don't require that. They check their blood sugars frequently. It's nice to have them check their blood sugars just to see where they're at. But you know, what I like to do with blood sugar taxes? I, you know, people will do blood sugar checks when they know that they have to respond to it. If you're just asking someone to do blood sugar checks three times a day, and they do nothing with that information. They're less likely to continue their blood sugars, so so people on pills. I don't necessarily ask that they check their blood sugars three times a day. But somebody who requires injections where they need to use that information to determine how much insulin to inject. We do require asked them to check it three to four times a day so type two diabetes. You hear more and more people talking about what you should try to prevent should try to stop from having. How do you prevent someone from getting diabetes? So one thing we do know is that lifestyle intervention can prevent the disease. Probably is the best thing we can do to prevent the disease. So obviously diet and exercise can and has been shown to prevent Taibbi eighties. Right. The problem is that most people can adhere to these types of regimens for only so long. So the reality is that what we're not doing is preventing. Disease delaying but a delays important. None the less. It's less time. You live with the disease. They're probably medications that can help as well. So met forms of medication that when used perhaps an individuals who have prediabetes can actually delay their progression to diabetes. What do you mean by prediabetes? So we defined diabetes, very strictly by blood sugars. So if your blood sugar is less than one hundred fasting in the morning, we say that's a normal blood sugar. If it's between one hundred one hundred twenty five we call that prediabetes. And if it's over one hundred twenty five we call that tubbies. So there are basically three different states. You could be and we know if you take all the people with prediabetes and diabetes combined. That's probably close to fifty percent of the US population dough my so fifty percent of all or is that fifty percent of adult, sir. Fifty percent of everybody overall. All in different age groups that can it can vary part of me, you know, the FDR saying well fifty percent people have something then it's normal. Yes. It's been increasing. Okay. It's been increasing. And so, you know, these data have been coming out from smaller scale studies that then are extrapolated into the US population. And so so a lot of them. Now, come from better data that that result from not just fasting blood sugar measurements. But from what we call oral glucose measurements. So we give somebody a a load of glucose, and you measure their blood sugar over time. And so many studies have collected these data, and when you go back, and you look at these data what you find. When you separate across age groups is that over the years, more and more people have been falling into the criteria of prediabetes and diabetes. So and many people don't know they have it. Right. When we say lifestyle changes, and we say diet and exercise we we talking about something radical. Or are we talking about, you know, exercise, the usual, thirty minutes a day five days a week and. Just eat healthy. That's basically what we're talk is. Always fascinated me. Because that's what we tell me what to do anyway. So what's the point of checking for prediabetes? And then tell be able to do it instead of just saying doing any, and I think that makes it great deal of sense. Absolutely. So you know, there are symptoms today. Beatty's? And so I think certainly if you're aware of those symptoms that you should definitely inform your doctor feeling thirsty all the time frequently urinating getting up in the middle of the night to urinate fatigue. Those are things that could be a sign of diabetes, but they may not show up so easily in many people because the disease just progresses over time. And so they don't notice these things happening. So, you know, obviously having a good lifestyle can prevent this. Do we screen everybody? No. We don't screen every you go and see your doctor two in the afternoon. We don't you're not fasting. When you walk in. So we don't do tasked routinely and people that says, hey, you have prediabetes. Diabetes. But there are some people in which you can probably predict might be at risk for prediabetes. Those are people who leave sedentary lifestyles were overweight. Those are individuals that you've probably can say, you know, there's a strong likelihood you could have prediabetes. And if you think you're going to do something about it could be worth checking, otherwise those people that you would say this is a good time to start leading a better lifestyle. Is there any diet? That's better than any other. So diet is very controversial area depends on who you talk to him. Right. There are some people that advocate, you know, low carb diets key Todic diets, there's a variety of different diets the American diabetes association, which is really sort of the, you know, the professional authority in this area has no specific. Conditions on which diet is better than another. Because the data are controversial anyone that you look at. I think the the bottom line is it's better to go with the diet that you can stick to right because you know, if you don't if you if you basically are being asked to take a, you know, a very high fat or high protein diet, and that's not what you normally eat the chances that you'll adhere to that or much lower. So where's the cutting edge stuff and type two diabetes right now. You know, a lot of the cutting edge stuff is in new medications right weight loss medications, we know that losing weight can have a dramatic impact on diabetes. So there are, you know, obviously, drug companies that are working on a variety of different than new drugs, and you probably know in the past decade, the number of new drugs for type two diabetes has been coming. Probably every. Couple of years there, obviously new drugs and the goal of many of these drugs is to lower blood sugar without increasing weight. And that's a big goal. The other goal and type two diabetes. Medications is that the FDA requires that many of them be tested longer term to look at risk for cardiovascular disease. Right. So we're not looking to reduce it. We're just looking to make sure these drugs don't increase that risk to have some of the ones in the past increase the rest. Yeah. There have been some in the past that suggest that it could increase risk again. A lot of its controversial. We sometimes look at the data and relocate the data. So there have been a class of drugs that we don't use very much called thighs Ola dean dions teasing dis. And at least one of those drugs has been suggested to increase the risk of heart failure that's concerning. And then when we re look at some of that data. It turns out. Well, maybe wasn't quite as convincing as we thought the first time, but there are some people that will say that. It's correct. There's some people say won't even something as simple as the cell finale RIA drugs that have been around for decades and large epidemiologic studies suggest they may increase the risk of heart disease. So so there's controversy that surrounds them. But one thing we do know from a lot of these studies that have been done with cardiovascular outcomes is that some of the newer drugs may actually reduce the risk of cardiovascular disease in addition to making your diabetes better. So the SGLT two inhibitors, for example, seem to lower the risk of what we call secondary, cardiovascular events does sort of obesity surgery help with type two diabetes. So that's another area. So what we call bariatric surgery? There's at least three different types of bariatric surgery. And at least two of those three seemed to be very effective in causing weight loss. But even before the loss in weight, we see dramatic improvements in diabetes. What is what are some things are labs working on? So our lab as I mentioned earlier has been interested in figuring out ways, we can cause insulin producing cells to regrow, and so we've been working on looking at the molecular pathways, and then seeing if we can identify new drugs that stimulate those pathways to cause these cells to grow the reason, I liked drugs is that for most drugs. They can induce the growth of beta cells, and then when you stop giving the drug the betas growth stars. So it has sort of a benefit that you can control, you know, how much and how long those cells regret so with type two or you trying more to stimulate the cells there as opposed to Richard describing before was to get sell the body that weren't there. And that's what we're trying. To because we know that they're they're they're they're good cells. They still secrete insulin. Really really we need to go. After those cells that are there, whereas type one you just don't have those cells can is it that we're working you're working on this animals is that where you are. So we're working on it in actually three different sort of model systems. If you well one is to or model systems on his not, but we're working on it in we start in zebra fish. So our lab, the the nice thing is the zebra fish have pancreas like humans do actually looks a lot like human panther. They produce insulin. They can get diabetes. And but the nice thing about zebra fish is that they allow us to screen for drugs. So if we have a hundred drugs that we think might have an impact do we want to be giving all those drugs to mice or pigs or large animals because that's expensive takes a lot of time. How do we screen? So what we do is. We screen zebra fish. We can screen thousands of of zebra fish in a very short time thousands of different drugs. How did just how is that something? You're lab, desserts is just the known zebra filter something that are let figuring out zebra fish. So other people have figured out zebra fish. We've been able to incorporate the technique in to our particular research, so zebra fish are really convenient because they develop on the order of days, mice take weeks and humans take years. So the nice thing about zebra fish is imagine the human compressed down to just three days. And that's the period of time that we can do an entire study in zebra. And then you just put in the drug in the water. That's all we do. That's fascinate, and the zebra fish are not the kind of fish that you see in your tank there the larva so that tiny little things that you can barely see with the naked eye, and but they have pancreas. They have. Insulin, and we have a variety of different colors that we are now able to take zebra fish with where we can color, the different cells. So we can actually see this growing in real time. We and the nice thing about zebra fish. They're translucent. You don't have to kill zebra fish, actually, look at its pancreas. So so you're not actually been sacrificing them to look at the Panthers or what we're watching them right under the scope in real time that it really is. It's really cool. And when we find drugs that work in that model system, we then like to move to mice mice are rate model system to work with they take longer, but we have good models of type one and type two diabetes in mice. And and I think that in the in the world of the pharmaceutical industry that is sort of the gold standard gotta show something in a mouse. And if you can show it in mouse, you don't often even have to go to any larger animals, you can go right to humans. How do you give the mice diabetes? So there's a couple of ways you can do it. So like in humans, you can cause a mouse to overeat. Okay. High fat diet they get obese and and they can get diabetes. That's that just like in humans and that takes about eight eight to sixteen weeks in that range to to get a mouse become diabetic. But that that's pretty good. And then we also have mice have a hyperactive immune system that killed their own insulin producing cells, and so they spontaneously developed diabetes after about, you know, fourteen eighteen weeks of age. So we know exactly when they're going to get diabetes. So we can do prevention studies or we can do curative studies in those animals depending on their age. And you said you had a third system is that different. Or is it? Well, the third system is humans. Okay. So we do studies in humans and an a great example was a study that I'm collaborating on with Linda Maglione, who's a pediatric endocrinologist who. Studies type one diabetes and believe it or not it started in zebra fish. So we identified a drug that is used today. Clinically in certain cancers that in zebra fish seemed to be protective of the insulin producing cells, and when we showed that we then moved into the mouse model, and we showed that we could feed these mice for four weeks for a period of time before they develop diabetes, then stop the feeding and then their risk of diabetes is reduced dramatically. And then because the drug is already on the market. And it's and it's marketed as a drug called f Florida theme we were able to use a low dose of that drug. Get file what's called a in a investigational new drug application to the FDA. And and then we did a dosing study in people. With diabetes and with the simple goal to find out. If we gave this drug for about six weeks in these individuals, can we see an improvement in insulin. Secretion do you? So we don't have the results back yet. The study is almost done. It was funded by the J D R F, and and it was done at three different sites. One here in Indianapolis, one in Milwaukee and one in buffalo, and and so those three sites recruited patients put them on the medication for six weeks. So we'll have that data probably by this time next year. It sounds like with the mouse model it was somewhat prevention as well though. I mean, yeah, that was what we were doing. So we're not doing a prevention study in humans, although that's the direction that a lot of people are going is in prevention studies, and what we did in this human study was asked to simple question, if it can prevent diabetes in the mouse because it protected the beta cells, which are the cells that produce insulin. Can we give? Them to humans with the disease and show some improvement in the function of those cells, and if we can then that would sit strongly suggest it could work, and then we would go and do perhaps a prevention study in this type two diabetes. This is type one. Oh, it's like one one. So so you're trying to bring back beta cells them from. Yeah. So that's interesting. So we're not trying to bring them back from death because that that would be hard to do. Right. But what we have learned with a lot of the studies we've done in humans in the past five years, we've been able to get pancreas from donors who've given their their pancreas to to sort of the scientific community after they passed away that even though we think of these cells all dead. They're not even somebody said diabetes for fifty years. There's actually insulin producing cells floating around not a lot. But they're they're in the pancreas. So they're not completely gone. And so what that means in our mind is that there's the potential to re-grow those cells. That's fascinating. How about just flat out Packers transplants? They worked pretty well. Pancreas transplants. Due reverse diabetes. There are some centers that do a lot of pancreas transplants are studs here in at you. And the people have had pancreas transplants. Of course, they have to be on immune suppression drugs, right because otherwise reject it. But those who've had a pancreas transplant on our stably on pink on that transplant are effectively cured of their diabetes. What about oral insulin? Can is there any movement in that? Yeah. So that's very interesting oral insulin. Insulin is not something we normally would give somebody or all right, right? You have to inject it. And the reason for that is that insulin protein. Yeah. And if you ingest a protein, your body breaks it up slow, right? But there is a thinking that that started many many years ago that suggests that if you can give somebody enough of it some small fragments of that insulin enter the bloodstream, and when it does it does something that call the is. Called tolerating the immune system. So that means that it it sort of educates the immune system to say, this is okay. The insulin. The insulin is okay. Don't don't go after it. Okay. So that it doesn't then go an attack the cells that produce it and that has been the thinking, so so it's a tolerance Asian technique. So it's not so much that you're taking the insulin to dose yourself within on us to teach the body to leave the pancreas. That's exactly what it home now works. So it's not. But there's been a lot of effort that's been put into that. There have been at least a couple of major trials the first trial. That was done. You know, you know, felt that well, maybe we just didn't use a large enough dose because it seemed like we might be there in in in preserving the the pancreas, but even the second trial that was done with a larger dose. There wasn't really a positive effect overall. And so I think. That a lot of the energy surrounding oral insulin is kind of fizzed out a bit. Where do we get all his insulin? When insulin was first discovered, the only place, you could get it was from animals, right? So pigs and cows. And so in the old days, they were you know, what we call beef and poor sign insulin. But even then did they have to sacrifice animal animal than just take what they could get in the pancreas, or would they have sort of them hooked up to machines and continental and get out, and it was all sacrificing the animals taking the paying out many of them would go to slaughter houses. Anyway, so you can take the pancreas out. And then literally you squeeze out the pancreas of all the insulin. That's in the and then you have to kind of crudely prepare it. And that's the reason why we dose insulin in units because in the old days when they made insulin. They didn't know how much they had because they had a lot of junk that came with the insulin. And so the only way they could measure insulin is by its activity and so. Now, we call that units and so ever since then we've kind of stuck to that dosing regimen. So we don't use milligram micrograms. Like, we do with every other we use the term units. Then, you know, a revolution came about in the seventies. When it was discovered that you can engineer bacteria and yeast and micro-organisms to actually produce the insulin and not only can they produce. So they can produce an insulin that identical to what humans produce. So now, you don't have to worry about, you know, not being able to take pig insulin because you have an allergic reaction to it. Right. So now, we produce human insulin. And then in the nineteen nineties came a new revolution. And that was well, you can take the human insulin you can tweak it a little bit. And when you do that you can change the way that insulin ax. Does it act fast? Does it act slow and so then ushered in in the nineties era of what? We call insulin analogs. And then now here we are in the two thousand two thousand tens almost everybody's on some form of human insulin analogue, or when did they figure out that we could take animal insulin and give it to human beings and inject them. And then this would work that happened in nineteen twenty two and I'm just like for a while just imagining it must have been incredibly difficult to to to engineer build up the system where you could produce enough insulin to actually treat decent numbers of people. So you know, that's where Indianapolis became famous. So the famous experiment was done by two researchers go panting. Invest in nineteen twenty one and they were able to take the pancreas out of a dog 'cause diabetes, and then extract the insulin from that pancreas and give it back to the dog and effectively in those days, they said cure the dog of diabetes. Right. And so they said, well, this should work in principle in humans and in nineteen twenty two the first Hugh. Human recipient received insulin in North America. And that was in the city of Rochester, New York, and and that that individual famous individuals names, James havens was the first recipient of this sort of insulin. And when word got out that the James havens, diabetes was, you know, quote, unquote, cured lily ally, Lillian company went to Toronto to effectively license the technique, and then to then bring it to the masses how many units of insulin. Can you get out of a cow's pancreas? That's a great question. Because again units are defined by actively. So it all depends on the size of the cow. You know, the technique that you use to isolate the insulin thinking like I started a magic how many cows they have to kill go. Probably, you know, they were you know, it's hard for me to say because we don't do it anymore. And I can't give you a number. Right now, there's about one hundred units per milliliter in a bottle of insulin. Oh, that's way, more than I thought. Imagine. Like, you get cowed kill it, Pinkus and ten units you'd get a lot more than that. Okay. Get a lot more than that. So right now, a bottle of insulin that you buy over the counter or not really over the counter. But in the pharmacy has a thousand units in it, so ten miles ten milliliters at one hundred units per milliliter tip. That's typical fastening. So why so expensive? Now, why is it like not just so easy to make cheap? It is easy to make it is relatively cheap. There's costs and production. There's Costin purification. There's cost and quality control. But they're not a, you know, unlike a lot of other drugs that go into the generic phase where it's produced by you know, you know, goes out of patent. It can be produced by anybody. And that brings the cost of these. Medications down not true with insulin's. There really are. No what we call. You know, third party, insulin producers, it's basically to comfort three companies in the country for the most part that produce insulin at Sanofi Novo and lily, and they kind of you know, are the only ones because they have gone through the trouble of setting up. You know, the fermenters that it takes to produce the bacteria or the yeast that produced the insulin, you know, and go through the entire process of quality control. Whereas, you know with many pills. It's not that difficult, right? Reduce right pills are easy to produce insulin's or more expensive. So we haven't really had any other players get into the game. And so what that means is that, you know, I it's largely the cost of insulin a largely controlled by three companies each company, and there's only three of them right now that produce these insulin's, you know, make insulin's that. Slightly different from one another and for different individuals. It's only that particular insulin that works really, well, we know why? Well, again, you know, it's because you know, everybody's a little bit different and their bodies react to these insulin's differently. Sometimes in some cases, it's, you know, some people have an allergic reaction to a particular insulin made by particular company. So they gotta go to somebody else that also some People's Insurance is, you know, have contracts which are companies, and and they'll say, they'll basically mandate, you know, if you want insurance coverage for this insulin you have to use this particular companies and Solent or this particular type of insulin from that company. No, I would imagine that this would be a market someone else would want to enter. Yes. But I think that there is an incredible up front cost in setting up the infrastructure to produce insulin at that at that sort of level. So somebody has to see that there is, you know, real. Value to be gained. I mean, this is a business. And and so the question is really is there going to be away to to pull one of these big companies, you know, off their thrown and then come in with a generic insulin. And I think there has been there's been encouragement for this. I think the FDA's encourage the government is encouraged, but there just aren't people willing to invest in it. So I think that that is a big challenge there is if I might add a company that is now here in Indianapolis that was brought in here by one of our recent recruits to the precision health initiative that I you his name is Michael Weiss, and Michael Weiss is world famous for deciphering, the structure of the insulin molecule, and and he started up a company with all the research that he's done where he has now produced what's called the heat. Table insulin. So this is an insulin. That doesn't have to be refrigerated consid- outdoors on your table. Top for months and still be fully active doesn't need to go in a refrigerator. So imagine what that means now to particularly parts of the world where refrigeration is not easily accessible is that it then becomes possible to give people insulin who could only get insulin under certain circumstances and certain times of the day. So that then you just need to engineer, the bacteria two to produce this particular kind of insulin fascinating. So given the many many options we've talked about today. How do you figure out which what each person needs personalized to them? So the precision health initiative, I use school medicine was really designed around not just looking at an individual and saying well based on everything that I know about you. This is the best therapy. That is. Really precision medicine that is just using good clinical site precision medicine is about really taking objective data on a patient. Not knowing anything about them personally, except for some data that you can obtain whether it's from their blood or maybe their weight or their height or something and say based on information that we have this is the best therapy for you because you're most likely to respond to this therapy. So part of that now is is about doing Geno mix studies. So let's let's just say that you had a clinical trial where you put somebody on drug a verses a placebo, and you found that there was a difference. And that the drug seemed to improve diabetes, but it only improve diabetes in a subset of people. There are still some people. Got the drug that didn't benefit, but the overall group showed a benefit right? So that's great. But that's still means that if I put somebody on that drug they may not respond, right? And so the question is how do you then teased down further to say, okay, that there are individuals within that group that didn't benefit and the reason they didn't benefit was because they had a particular gene that every time somebody didn't respond was associated with that, gene. Right. Right. So precision health can be interpreted in a way that says, hey, if we can sequence all jeans, and you're in your in your body, we can do that relatively inexpensive. Now, can we find a combination of genes that we know that you have that would say you just need to be on this medication or this medication? And the likelihood that you'll respond very very high, and we're working towards that. We don't have that. Now, we don't have that. Now, we're working towards that. So what the? Precision health initiative is about is taking maybe samples that have been stored from studies like that, right? And then doing not just genomics, but what we call functional genomics. It's not just the genes that you have. But the genes that are active or even other proteins that are circulating in your body. And using a combination of all of the stuff using what we call informatics to then tease out. You know, a quintessential set of what's called the markers that would suggest you would respond or not respond to a specific therapy. And knowing all that information, we could say that you should be on a combination of this pill and this pill, and then it's likely in six years, you're going to need this pill or you're going to need this injection. How far are we away from that? So I think we're probably a lot closer to that than we might think because we have the technologies to do all the genomics and functional genomics, we have, you know, blood and urine and other things stored up. From multiple clinical trials that you don't have to actually start a new trial. This you can actually go to the freezer banks, and then do these kinds of studies. And so, you know, you know, we have a very large bio Bank here in Indiana, Indiana, Via Banque that has stored a lot of tissue samples blood urine from people from different studies. And we have other trials that are ongoing here Indiana University where we've done that precision health initiative in part with in terms of diabetes is about going to those banks without actually doing all the studies over again and saying, you know, what can we learn today with the technology. We have now from a study that might have been done ten years ago. And so that's going on now that is going on now. Well, we'll look forward to hearing results in the future excited to report on them to regulate. Thank you so much for joining us learned to done as I said before as more results come out. We'd love to have you back. My pleasure. Thank you for having me.

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