This Podcast Will Kill You - Ep 83 Diabetes: Short & Sweet

Episode Date: October 5, 2021

Almost everyone is familiar with diabetes mellitus in some way. Whether we know family or friends that have been diagnosed with the condition or we’re directly impacted ourselves, diabetes mellitus has become a household name. And this is perhaps not surprising given its extremely high prevalence - nearly 9% of adults around the globe are estimated to live with the disease. But although we may know someone with diabetes, how much do we know about diabetes itself? How does it work? Why does it cause the acute symptoms and long-term complications it does? Where does an infamous scientific rivalry fit into the story of diabetes? How long have humans been dealing with this disease, and how far has treatment come since the early days of diabetes? And importantly, how has our perception and portrayal of diabetes changed over the course of its history? In this episode, we seek to answer all these questions and many more about the globally-prevalent diabetes mellitus. See omnystudio.com/listener for privacy information.

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Selection varies by location. Order by 4 p.m. Available Monday through Saturday. Subject to availability. Fees, exclusions, and restrictions apply. See loaves.com slash appliance delivery for more details. Visit your nearby lows on Renier Avenue South in Seattle. Comcast business helps retailers become seamlessly restocking, frictionless paying favorite shopping destinations.

Thank you for shopping. It's how nationwide restaurants become touchscreen ordering, quick-serving eateries, and how hospitals become the patient-scanning, data-managing, health care facilities that we all depend on. With leading networking and connectivity, advanced cybersecurity and expert partnership, Comcast Business is powering the engine of modern business. Powering possibilities. Restrictions apply. Hi, I'm Carla Williamson. I am a type 1 diabetic, 43 years this August.

I was diagnosed in 1977. I was drinking all the time. I cannot get enough water. My mom said I would go from a water fountain, drink a Coke, then drink milk. I couldn't get enough. I was losing weight. My dad was a type 1 diabetic also, and my mom had recognized the symptoms pretty early.

And back then, they did not have home blood glucose monitoring. So I was out doing yard work, and my dad came home for lunch, and they called me in the house and said, go in the bathroom, and I want you to use the restroom on this litmus paper. And I went to the restroom, urinated on the litmus paper, and it turned bright blue.

which I knew and my parents knew them that I was a diabetic. So I got diagnosed in the summer before sixth grade. So I started a new middle school. I had one other classmate that was also a diabetic, but I was really embarrassed to tell anybody. I didn't want anybody to know. So if I had a low blood sugar, I wouldn't want to tell anybody.

So I would wait until I was like in a dead sweat and almost out of it, my teacher would say something because she would keep orange juice in her desk. but I did not want to be called out or tell anybody. I didn't want to be different than anybody. It was not until I was a nurse working in a hospital. I had a friend that was also on a pump, you know, and we started talking, and I loved talking about it, and I loved educating.

And I found even now that I'm a school nurse, talking to kids with diabetes and letting them see that you can live a normal life and you're not any different than anybody else. You can do anything you want and live with this disease, but you have to acknowledge it and take care of it is huge. And I love playing that role now. So growing up, my friends were very understanding. You know, you would go over and parents would be very scared to have you over because they were like, oh, gosh, she's a diabetic. How do we take care of someone with diabetes?

And my mom would say, she can take care of it. She knows what to do. my parents handed me the disease at 10 years old and said, this is yours, you're going to live with the rest of your life. You've got to learn to make good decisions. So I got out of the hospital on a Monday and I was at a sleepover on a Friday. So I was always given freedoms and good or bad. I don't know, but to handle this disease. Back in 1977, it's so different than it is now. Everything was no sugar. You could eat anything you wanted. You just couldn't have sugar. It was one shot a day.

It was all long acting insulin. It was beef and pork based insulin back then. So control was not good. Being 10, number one, but also, you know, just no way to monitor what you're doing. You peed on a keto strip that showed glucose and ketones. And then you went to the doctor and had blood work done. And he always said, you're not in control. You're awful.

You're going to be dead before you're 30. you know, you've got to take care of yourself. So it was not a good thing to hear when you're, you know, 11 years old, 10, 11 years old. So I was never well controlled. At 16, I went into a diabetic coma for four days. During that, they found that I was immune to the beef and pork insulin. And thankfully, at that time, they had developed the humulin insulin. So they put me on humulin in, or NPH, which is a buffer, long-acting insulin and humulin R, which is a regular short acting insulin. But even then, it was just two shots a day. Everything was still based on, you know, sugars, not carbs. Really, the concept was not there yet for that. So when I was in college, I was in DCA like every semester, or drank too much. You think you're taking your two shots a day. You're going to be fine. when I was 19 years old in 1987, I told my mom, I think I'm dying. I don't feel good.

I feel horrible. She said, you're a lazy teenager. And I found a doctor and I said, I don't feel good. I'm taking my insulin. I don't feel good. He put me in the hospital right away and I was immune to all buffered insulin. So in 1987, my life changed forever because I got placed on an insulin pump. I have been under tight control ever since.

I just think it's come a long way. I think pump therapy, now I'm on a sensor. They come out with sensor therapy. So it reads your blood sugar all the time. You have so much more freedom now. Just coming from someone from 43 years of having diabetes, I will never complain that I have it. Like, it is part of me. It's who I am. But diabetes is huge. It changes every aspect of your life. You have to think about everything before you do it. You just have to be prepared for high blood sugar, low blood sugars, you have to be able to have a positive attitude and not ignore it. You can't ignore it. And you have to take care of yourself. Thank you so much, Carla, for coming on and chatting with us. We really appreciate it. We do. Hi, I'm Erin Welsh. And I'm Aaron Almond Updike. And this is,

this podcast will kill you. Yeah. This is going to be a good episode, Aaron. I think so. I think it's I mean, we say this every time. This is this podcast, and we are excited about this episode, and it's going to be a good one, and we can't wait to get into it. Yeah. You know, we're going to try and keep it short and sweet, right? Yeah, but we will fail in our attempt. Should we start off with a quarantini?

Let's do it. What are we drinking this week, Aaron? This week, I can barely hold in the laughter. This week, we are drinking the aptly named Sweet Pea. The sweet pee. It's spelled P-E-E. Yeah. Get it?

Aaron, do you want to explain why we're calling it sweet pee? Well, I'll explain a lot in the biology section, but that is one of the hallmark symptoms of diabetes, mellitus. which is the topic of today, and that's having excess glucose or sugar in your pee. Yeah, it's true. But unlike that pee, sweet pee, the quarantini and placebo,ita, does not have any sugar in it. No, it's diabetes-friendly. Yeah. The thing is, we were, you know, researching, okay, what are good cocktails for people with diabetes?

And, you know, again and again, it kind of came up as like no sugar, you know, pretty simple stuff. And so what we wanted to do was kind of keep it simple and approachable. And it's actually one of my favorite, like, go-to drinks. It's a vodka soda. It's a vodka soda. And if you want the Plessy Barita version, it's a soda water with lime. Yeah. And the thing is, you know, you can really, you know, spice it up or flavor it up however you want to do it, right?

You can use infused vodka. You can use lemon or a different kind of fruit instead of lime. You can do anything you want. You can do stevia syrup or whatever. But, you know, as a baseline, start with a vodka soda. Yeah, do that. If you need a full recipe, we will post one on our website. This podcast will kill you.com and all of our social media channels.

So more business. On our website, you can also find things like transcripts. You can find things like a link to our Goodreads list to all. our bookshop.org affiliate account. You can find all of the references to past episodes, promo codes for all of the things we talk about in the ads. What else, Erin? Oh, everything.

Everything you need. This podcast will kill you.com. Oh, yeah. Merch and music. Two more things. I feel like at this point in the season and in our podcasting career, we should have that part down, but somehow we don't. We never do.

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So here's the thing about, diabetes, Aaron. We always say that we're not experts on any of the topics that we cover. True. And it's still true here today. So certainly there are probably going to be like endocrinologists or PhDs in biochemistry who are like, you're missing crucial pieces. We're focusing here on the broad strokes, folks. So what I'm hoping that listeners come away with by the end of this episode is an understanding from the biology side of what insolven insulin is and what it normally does, what the essential underlying problems are in diabetes, whatever type we talk about, and why you see the complications that you see. So those are the three

main pictures, okay? Excellent. All right. So let's start with some basic physiology. When a person eats like a meal, okay, when you just take a meal, you chew up your food, you swallow it, you digest it. It goes through your small intestine, blah, blah, blah, breaks down into simple sugars, proteins break down into amino acids, we absorb them through our gut, right? We've covered that a lot on this podcast because we've talked about a lot of gut bugs, but usually that's where we end the conversation is after things get absorbed or don't get absorbed into our bloodstream. So now we're going to talk about everything that happens after that. So in our bloodstream, these nutrients, sugars, amino acids, fatty acids, these are what our cells use for energy so that we can live and grow

and exist. And one of those sources of energy that our cells use is glucose, which is a single sugar, like a one sugar molecule. A lot of tissues use other sources of energy more than glucose, but some of our tissues, including our brain, can pretty much only use glucose. And the way that this gets to our tissues is through our bloodstream. And so that's what we call plasma glucose. That's like the primary source of fuel for our brain and some other tissues. And it turns out for reasons that we'll talk about later on, it's very important for our bodies to keep really tight control on our plasma glucose levels. So the amount of sugar in your blood has to be really tightly controlled so that it doesn't go too high or too low. But the problem then is that the majority

of our intake of energy, like when we eat, happens in discrete time periods. It's not like we're eating continuously throughout the day. We have periods like overnight where we don't eat at all. And then periods like, I don't know, Thanksgiving where we eat way too much all at once. So our body has to have mechanisms to store excess glucose, like we're. right after we eat a meal, and then also to liberate glucose from storage so that it's available in our bloodstream when we haven't eaten or when we're fasting. And it has to be able to do this in a very narrow window of healthy plasma glucose levels. We can't let the blood sugars get too high and they also can't get too low. So the question is, how do we do this in our bodies? The answer is

insulin. Can we have like a trumpet play whenever I say insulin in this episode? That would be a lot of trumpeting, I think. Way too many trumpets. So insulin is a peptide that is synthesized in the pancreas. Your pancreas is just a really incredible organ. It excretes a lot of digestive enzymes that allow the breakdown of nutrients and then a whole range of different hormones that enter the bloodstream and have a variety of effects. But one of these major hormones is insulin. And it's secreted specifically by these cells called beta cells in response to elevated blood glucose levels. And insulin has three or kind of four major effects. Number one, what it does is suppress the release of glucose from the liver, which is one of the main storage sites for extra

sugar. It also turns on glucose transporters on our muscle tissue and our adipose tissue so that that glucose can actually get into our cells and then be stored or used. And it also stimulates glycogen synthesis, which is the way that our body stores glucose. And it does so much. It also inhibits the release of free fatty acids, which are another one of the major forms of energy that our body uses. And it stimulates those to be stored instead. So we store fat when we have insulin secretion. Okay. Gotcha. All right. That was a lot. I know. But the like TLDR of all of that is that insulin is a hormone that is secreted when glucose levels are high. And insulin's role is to decrease plasma or blood levels of glucose in our bodies.

This is like flashback from teaching IB 150 or 151 or whatever it is. Yeah. It's like way back intro biochem. Oh yeah. But I haven't even gotten to diabetes. Right. So the question is what is diabetes? And at its core, diabetes is a problem of insulin. I think that a lot of people think of diabetes in terms of glucose. They're like diabetes, sugar, blah, blah, blah. But diabetes is a problem of insulin. So if insulin's normal function is to decrease blood levels of glucose, and diabetes is a problem where insulin isn't working correctly, then the problem in diabetes is you have too much glucose

in your bloodstream. Right. Right. So now the episode's over and you understand everything about diabetes. Uh-huh. Okay. Obviously, that's not true. We're going to choose your own adventure a little bit here.

Okay. Okay. Are you ready for this? Because there's two things that we still need to understand. We need to understand why it's a problem that glucose levels get too high. Like what is it that's happening? Why is that problematic? And then we also need to know how does diabetes actually happen?

Like, what is the essential problem in this pathway with insulin and glucose? Right. So which do you want to go over first? Well, I think the problems. Okay, like what happens with the problem with insulin? Yeah, exactly. Okay, great. Great answer, Aaron.

Everyone is probably well aware that there are multiple different types of diabetes, which have a number of different names that I'm guessing you're probably going to go to in a little bit, right, Aaron? I mean, only actually very briefly. Okay, that's fine. For most of the history, I just say diabetes. Oh, that's fair. Well, the different types of diabetes, it is really important to understand the distinctions between them, so we'll go over it here. But essentially, the way that we classify it today is type 1 diabetes, type 2 diabetes, and then there's like gestational diabetes, and there's a few of it. are more rare forms. So we're going to focus on type 1 and type 2. So type 1 diabetes,

in general, results from a destruction of the beta cells of the pancreas, usually from auto-antibodies. So type 1 diabetes is an autoimmune condition where our bodies start to make antibodies against our own pancreas' beta cells, which are so important because they produce and secrete insulin and these antibodies destroy those beta cells. What do we know of the triggers for this autoimmune reaction? Really good question, Aaron. We don't. Okay. So there is a genetic component to type one diabetes. However, what is interesting is that the genetic links with type 1 diabetes, it's not like a hereditary disease.

So the genetic links are not nearly as strong, actually, as in type 2 diabetes, for example. Oh, interesting. Yeah. So while there are these genetic factors that certainly play a role, it's also environmental factors. And we don't know exactly what those environmental factors are that then lead to this autoimmune disease. There's a lot of thought that maybe it's viral involvement, like in people with certain susceptible genotypes, exposure to certain viruses or certain other environmental conditions trigger this autoimmune response that then leads to type 1 diabetes.

Which viruses? Great question. We don't know. People have proposed, like, name a virus, it's probably been proposed as a potential cause, especially viruses that are really common. Epstein bar, definitely. CMV, absolutely all of them. I was going to say CMV was my next one.

Influenza. Yeah. Influenza, I think, has been on that list, too. But nothing that's like a strong association to be able to pin down one specific virus. Hmm. Yeah. But in short, because of this, type 1 diabetes results from a complete inability to make insulin. So no insulin in your body means nothing to bring down those blood glucose levels,

nothing to signal your body to store that glucose or allow that glucose into ourselves so that we can actually use it. And for the most part, this disease tends to happen on a pretty quick time scale, especially when it happens in kids or adolescents, like the process of starting to generate these antibodies and then the slow destruction of these beta cells and then the onset of diabetes symptoms happens pretty rapidly. It can happen in adults as well, and then it tends to be a bit slower of a course, and we don't know why. Okay. So that's type 1 diabetes and kind of the underlying causes. You look like you have a question. Well, I don't know if it's something that you're going to go over in the other path of my choose-my-own-adventure. Well, okay, then let's wait, and if you still have it at the end, then ask it.

Okay. Just like in class. Hold all questions until the end of the presentation, please. And then it'll be more of a comment. Yep. All right. So type 2 diabetes. It's a bit more complicated than that.

Type 2 diabetes results from a combination of different things, including beta cell dysfunction, but not necessarily destruction. What's the difference between dysfunction and disruption? Just like producing less insulin? Right. Yeah. So either producing like not great insulin or just not being able to produce enough insulin or making insulin but not being able to secrete it.

Whereas in type 1 diabetes, your beta cells are obliterated. They're gone. Right. Okay. Yeah. So it's a combination of beta cell dysfunction and insulin resistance. So you have insulin. You're making insulin, but your tissues are not responding to it the way that they're

supposed to. So what does that really mean? Right. It means that in general, people with type 2-dine, diabetes have either one or both of two different problems going on. Problem one, like I said, their beta cells are not making enough insulin. For whatever reason, they just stop being able to produce enough insulin or secrete that insulin into this bloodstream. Or problem number two, their tissues become resistant to these effects. So then the pancreas secretes more and more

insulin. So what we actually see is a hyper-insulinemia. That means you have a lot of insulin in your bloodstream, but it's not being used properly. And so it's not effective. And therefore, you still have too much glucose in your bloodstream. So you just have like a bunch of like insulin and glucose, you know, circulating around. So what does it mean that your tissues are no longer responding to insulin in the right way? Like what's going on there? Yeah, good question. A whole whole bunch of different things. In part, it's that you actually can see down regulation of the number of glucose receptors on tissues. So glucose has to be actively transported into your skeletal muscle and your adipose tissue. It can't just like wiggle its way in there. And so in type two diabetes,

you can have less receptors on those cells, like they progressively get lower. Or like a whole host of other things can happen. But that's kind of the main ones. But why? Okay, we'll get to the why. Okay. Hopefully. Maybe. Maybe. Okay. We'll approach the why. But yeah, we'll slowly get to the why. But one question, because in many cases, we actually see both of these things happening simultaneously. So then there comes this question of which comes first. So the way that I like to think of it, and again, This is very simplified, but I think it's kind of just a nice framework to have, is that as you start to have this increase in insulin resistance, so your tissues are down-regulating the amount of receptors that they have so that the glucose can't get into the tissues.

You have an increase in insulin resistance, and your pancreas recognizes this, and it's like, gosh, we have just so much glucose running around, so your pancreas is working around. So your pancreas is working really hard, like working overtime to make more and more insulin. And that then causes your tissues to become even more desensitized to that insulin because they're just overloaded. It's like insulin overload. There's so much of it. So then your pancreas makes even more. And then eventually your pancreas is just exhausted because it's been working overtime for so long that it starts to just give up.

And then either making cruddy insulin or just not making insulin or not making insulin or not. not secreting it. Like, what's the point? You're not going to even respond to it. I'm going to quit. So now you have both problem one and problem two, problem two, exacerbating problem one and causing this vicious cycle. What's the timeline for that to happen? That's a good question. And it's hard to put an actual timeline on it, especially because when you look at like a population level, there are a whole lot of people who have what is sometimes called pre-diabetes or just, I forget the other proper term for it, but it's like increased fasting glucose levels where they have this higher than what is considered typical baseline glucose. And so some of those people will then progress to type two diabetes.

Some people won't. And some people have like both problems going on. Some people maybe have only a little of one. So type two diabetes is very complicated. Interesting. And so when it comes to type two, part of the problem is like the resistance seems like the biggest part to target for treatment, right? Like how do you reduce resistance? Because it seems like that sort of what's contributing to the pancreas just being overloaded and like, poof, I can't do this anymore. Yeah, that's a good thought. And we actually have a lot of medicines that do exactly that to try and make your tissues more sensitive to the effects of insulin. And that is for some people really good treatment for diabetes. But we'll just have to keep talking because there's more to the story. Excellent.

Love that song, my favorite track. I just made it up. Just right off the top of my head. All right. So now let's talk, now that we understand the underlying problem with these two different types of diabetes, let's talk about what the symptoms of these diseases are. And then we'll finally get to that second part of the Choose Your Own Adventure, which is like understanding why this high glucose is a problem. Because that really is what drives the symptoms.

Right. So classically, especially with type 1 diabetes, however, all of these symptoms that I'm going to talk about can happen with type 1 or type 2 diabetes. But because type 1 tends to happen faster and type 2 tends to be a much longer course, the more acute symptoms tend to happen more in type 1 diabetes, and the chronic complications can happen in both, but certainly in type 2 diabetes. So classically, somebody with diabetes presents with what is often called the three peas, that is polyurea, polydipsia, and polyphasia, and also weight loss.

So what do those mean and how does it happen? So as your blood glucose levels rise, eventually your kidney, which is responsible for filtering everything in your blood, just can't filter all of that glucose and get it back into your bloodstream because there's just so much of it. So your kidney starts excreting glucose after your blood levels reach about 180. It just starts, you start peeing out sugar. Hence the name of our quarantini. I mean, sweet pee. And glucose, just like lack of lack of it. Lactose does in our guts, see our lactose intolerance episode, glucose is an osmotic diuretic, so it holds onto the water along with it. So now you're peeing out a ton of water because your kidneys

aren't holding on to the glucose or the water. So that's the first pee, polyurea, which leads, unsurprisingly, to massive dehydration causing the second pea polydipsia, which means major increase in thirst, like unquenchable thirst. And at the same time, the lack of insulin in your body, which is driving all of this, essentially means that your body is unable to use any of the glucose that you have in your bloodstream. So while you technically have plenty of fuel, your body thinks that it's in starvation mode. And so it switches to what's called catabolic metabolism, and that is breaking down your tissues to use for fuel, which leads to major hunger, that is polyphasia, the third P. But despite this, you see weight loss because you're literally eating your own body tissues to use as fuel.

Really, really bad things. Very bad things. And then you have other symptoms like fatigue, unsurprising, because this is taking a major toll on your body, blurry vision, muscle cramps because your electrolytes are. way out of whack, et cetera. And when this gets very severe, which happens in about 20 to 40% of cases in people like presenting for the first time with something like type 1 diabetes, it's called diabetic ketoacidosis. A lot of people have probably heard of this. It is exactly what the name implies. So I just looked this up to clarify something that I had popped into my head. And I remember,

do you ever see the movie Steele Magnolias with Julia Roberts? I have never seen Stile Magnolias. Okay. Well, you know, I hope this isn't too much of a spoiler, but there's definitely Julia Roberts plays someone who has type 1 diabetes. And there's like, I thought it was a keto Acidosis, like attack. No, it was actually hypoglycemia. But I need to rewatch that movie now after doing this episode. Well, you saying that just made me think of honey, I shrunk the, is it honey we shrunk ourselves? I think it's number three. Yeah. Or no, number three is the baby. But I don't remember what happened in that. He needs bananas because of the potassium. But is that because he's diabetic? Because you do need potassium. I think so.

I don't know. Anyways. That has nothing to do it. There are many of them, I believe. All right. So, diabetic ketoacidosis. So if you're thinking about that classic presentation that I talked about, as that can kind of progress, if it goes unrecognized, or if somebody has like a low level of that going on, the three peas, and then they get some other stressor on top of it, like an infection

or just something that stresses their body out, as that person becomes even more dehydrated and just continue this process of breaking down their fat stores, their liver then starts this process of ketogenesis. Ketones can be used by the brain as an alternative source of fuel. However, they are in acid and therefore lead to the blood becoming acidotic, which because of dehydration is compensated. compounded by lactic acidosis, which then further worsens kidney function, which makes it even

harder to excrete those keto acids because that's one of your kidney's jobs. And this acinemia can eventually lead to brain damage. And on top of that, your body compensates via respiration to try and make your blood alkalotic by something called Kusmal breathing, which is essentially hyperventilation, which can then lead to coma and death. It's very severe. Okay, so when people refer to a diabetic coma, it's ketoacidosis, like... It's very often, yes, it can be. Okay. Yeah. So that's kind of the acute complications of diabetes, type 1 or type 2, but those tend to happen more in type 1, but certainly somebody with undiagnosed type 2 diabetes might have symptoms like a little bit of polydipsia,

maybe some polyurea, et cetera. So now let's think of it in terms of long-term. Why is having too much sugar in your blood bad long-term? And a lot of people might know of some of the common kind of side effects of diabetes. Aaron, do you know some of them just off the top of your head? I mean, I know that kidney disease is a big problem. I know ulcers are a big problem. Like amputations are really common.

blindness or retinopathy is really common. I think just like loss of sensation in your extremities. Yeah. Yeah. Peripheral neuropathy. Yeah. And all of those things that you just talked about, plus the cardiovascular risk. So risk of clots, especially in your heart or your brain. Right. Heart attacks are really common too. Yeah. All of those can be split into kind of two different but very similar processes. Those are microvascular complications, so small blood vessel problems, and macrovascular complications, so large blood vessels, heart, brain. Okay. But either way,

we're dealing with vascular complications, and in some cases, direct damage to nerves as well as blood vessels. So the question is, like, how exactly do these complications occur, and that is probably the subject of many different PhDs worth of research. But in general, chronically, having way too much glucose in your bloodstream leads to a state of chronic inflammation. This then leads to the production of reactive oxygen species, which we've talked about a number of times on the podcast, which are basically things that then cause a bunch of tissue

damage, especially in blood vessels, causing vascular injury. And that can lead to all of those complications that you mentioned, Aaron. So it has major effects on the kidneys, especially if you think about it, this is where all of that glucose is going, and the kidneys are filtering everything in your bloodstream. So kidney damage is a major one. Blindness is caused from retinopathy, where you have damage to the nerves of the eye and also increased blood vessel formation that leads to increase pressures behind the eye. The peripheral neuropathies, which can lead to a loss of sensation that can then lead to injuries that are complicated by poor perfusion because those blood vessels are damaged, so then those ulcers don't heal because they don't have any blood flow,

so then they become gangrenous, and then yes, you have to do amputations. It's a It seems like there are parts of the body that are more sensitive to this. Kidneys make sense because they're having a difficult time with the filtration. Heart makes sense because blood, blah, blah, blah. What about like your stomach or like, you know, other organs? I mean, what's going on with those? Yeah, great question. I think a lot of people think that diabetes, oh, your kidneys, your eyes, diabetes is a disease that affects every single organ in your body. So your stomach, diabetes can affect your autonomic nervous system as well as your peripheral nerves. And that damage, along with a host of other things, can lead to delayed gastric emptying. So it can cause your stomach to not be able to

contract the way that it's supposed to so that you can actually get your food to empty from your stomach, which can lead to a whole host of problems. So yeah, diet. diabetes affects every part of your body. It has the greatest effects and the earliest effects on small blood vessels. That's why we see things like neuropathy or retinopathy because those are really small vessels. But then it also has the potential to have complications on larger vessels like your heart, your brain. It affects the entirety of your body. Yeah. Okay. That makes sense. And that's the biology of diabetes, Erin. Did we get to the why? I've been waiting. I know. You have been waiting. We don't have a great answer to the why, but I have a guess as to the

answer in our current event section, so we'll just have to wait. Oh, okay. All right. Okay. So, Erin, tell me, what do we know about this? I assume it's been with us since forever. Yeah, let's start back at forever right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's working hands hand cream is such a relief.

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refresh rooms, and win the hearts of the judges. Bachelor Mansion... Bachelor Mansion Takeover, Special Series Monday at 8 on HGTV. All right. So, this is a long episode so far. And I'm going to add to that. I'm going to do something a little bit different for this episode. And that is to divide the history section into two parts.

Okay. Not like sequential chapters, you know, like this happened and then this happened, but more like parallel histories in a way. Awesome. And for this first part, I'm going to focus on the standard history that I usually cover for a disease, you know, things like early writings, increasing recognition of the condition, and medical advancements, especially when it comes to diabetes, the discovery of insulin.

You know, all the things that, like, completely changed the landscape of diabetes, especially in the 20th century. And then for part two, I really want to go through the other transformation that diabetes went through around that same time. And that is the social perception or portrayal of the disease. especially focusing on the U.S. Excellent. I can't wait.

All righty. So let's begin at the beginning. It probably doesn't surprise you to know that diabetes has long been recognized by many different ancient cultures. You went through the symptoms of diabetes and especially for the acute symptoms. And they're pretty recognizable and unique. So it makes sense that they were written about at length for thousands of years. It was mentioned in the Ebers Papyrus, our favorite, in the form of a treatment for a symptom of the disease. So, quote, a medicine to drive away the passing of too much urine.

And in the 6th century BCE, the Hindu physician Sushruda described a disease of honey urine, which could be detected either through tasting it directly or by observing ants gathering around a pool of urine. Ooh. Yeah. And the word diabetes itself comes from the second century CE when the ancient Greek physician Eritus coined it from the Greek word for to run through or pipe-like. He also described the disease as, quote, melting down of the flesh and limbs into urine. And the word meletus from the Latin word for honey or sweet was added later on to, again, indicate the sweetness of the urine. Galen, around the same time as Eritus, described it as, quote, diarrhea of urine.

And Avicenna in the 10th century, CE, wrote a thorough description of the disease and its complications. So the sweetness of the urine had long been recognized, the sweet pea. was people were very familiar with it. But it wasn't until the 1600s that a physician in Liverpool named Matthew Dobson realized that it was actually sugar causing the sweetness. He made the observation when treating a patient who was urinating 15 liters of fluid a day. Oh, my. Just to like, because I think when we say, oh, you pee a lot, like, what does that actually mean?

Right. And so this person was peeing 15 liters. of fluid a day. That is way too much. Oh yeah. We just had a little... We had a little sidebar to do a little calculation. It was really boring, so we had to cut it.

But for reference, a typical amount of urine output is between 800 and about 2,000 milliliters or two liters a day. A day. So compare that to 15. Yeah. Oh. Yeah.

So we've been talking about sweet pee. And yeah, I mean, people did have to taste it. Like that was how a lot of the diagnoses were made or, you know, mostly were made. But at least one doctor successfully fermented the urine to produce what he described as like a weak beer. urine beer? That should have been our quarantini. That should have been our quarantini. And this taste test remained the main way of diagnosing someone with diabetes until the 1800s, when chemical tests were developed to detect and measure glucose in the urine, much to many physicians' relief, I am sure. Around the time that these tests were developed, the medical world was

undergoing a pretty big transformation in terms of our understanding of disease. Yes, I'm bringing up germ theory in the history of diabetes. Oh, okay. But as researchers and clinicians learned about infectious diseases and applied that knowledge to prevention, a lot of chronic diseases grew more visible as morbidity and mortality from infectious diseases dropped. Right? And when they did, they grabbed some. research attention to themselves. So from the middle of the 1800s, it was increasingly recognized that the pancreas played some role in the disease, thanks to the rise in autopsies that had, you know, been happening, that showed that damaged pancreas were often found in people

with diabetes. And in 1889, at the University of Strasbourg, two researchers named Oscar Minkowski and Joseph von Mering showed this experimentally that the pancreas was involved when they induced diabetes in a dog after removing its pancreas. And it like was all over the, like peeing everywhere in the lab. And it'll do it. Mankowski was like, what's going on? I'm so annoyed. This dog is house trained.

Why is it peeing everywhere? Oh my gosh, it has diabetes. But how exactly was the pancreas involved? What was happening? Additional experiments removing part of the pancreas or grafting, you know, bits of a pancreas showed eventually that the pancreas seemed to have two secretions. One external that seemed to help with digestion and one internal that went right into the bloodstream to help with carbohydrate regulation.

But where did the internal secretion come from? In 1901, Eugene Opie at Johns Hopkins showed that damage to the islets of Langerhans, which were named for their discoverer, that that damage prevented the production of this internal secretion, which then led researchers to speculate that if this internal secretion, which, by the way, was totally hypothetical at the time, if it could be isolated, it could potentially be used to treat diabetes. This is so cool, Aaron. It is amazing that people, I just can't believe, like the pancreas, like the functions of the pancreas at a time when, like, bioassays were non-existent. Right. It's just people being so kind of intuitive or maybe it's deductive. I don't know. But it's just, it's smarter than me.

I'm so impressed by it. Well, I think also, you know, to give a little bit more historical context at the time, this wasn't necessarily as huge a leap in thinking as we are looking at it to be, right? This was actually in line with a lot of other medical advancements that were happening, showing how certain organs produced hormones. Like the field of, you know, endocrinology was kind of burgeoning at this time. and that it was recognized that these hormones regulated bodily functions and disruptions in the production of these hormones could then lead to certain diseases.

Especially once like, you know, germ theory was like, all right, let's do the low-hanging fruit. We got all these diseases. Okay, what are all these now? Yeah. What's happening? And then in the 1890s, it was found that giving someone like thyroid extract could, actually help treat some conditions. So in this line of reasoning, it made sense that pancreas extract could possibly do the same. But early experiments with these pancreas extracts that were performed around the

very early 1900s on humans had, you know, mixed results. Unsurprising. If I'm feeling generous, yep. Okay. And if I'm not feeling generous, I would say mostly harmful and sometimes outright dangerous. But in any case, they didn't really suggest that this was like a good path forward. Like this was not the clear way to go. So what was? Well, despite the growing visibility of diabetes and all these advancements in understanding its pathology and being able to diagnose it, one area that was sorely lacking was in treatment. Throughout the 1700s and much of the 1800s, the leading treatments for diabetes were basically the same things that you would use to treat anything, right?

Bleed them and shoot them up with opium. Like, that, boom, if you know how to do those things, you're a doctor in the 1700s. And there are very few diseases that would actually benefit from bleeding, but they do exist, hemacromatosis. But diabetes is not one of these. Yeah. And opium, of course, that isn't going to make diabetes or many things better. Nope, no.

Diabetes was generally viewed as a disease of downhill progress. And for someone diagnosed with what was then known as acute or juvenile onset diabetes now type 1, the life expectancy following diagnosis was like one to three years. Yeah. Often it was months. Yeah. It wasn't that much longer for those with, you know, what was viewed as the chronic form either. It was essentially a death sentence.

Yeah. Like across the board. Medications and tinctures and infusions seemed to be of no help for the disease, but there was one thing that seemed to slow the progression of the disease maybe, even though it did nothing to cure it. Starvation diets. Oh, yeah. Mm-hmm, yeah. So during the 1870 siege of Paris, when food was rationed and many people were near starvation,

one doctor noticed that the urine of some of his patients with diabetes had dropped in their glucose levels and that their symptoms had begun to improve a little bit. So the logical step was, well, if we severely limit the caloric intake of people with diabetes, we can reduce the symptoms of the disease. And this was the opposite of previous thinking, which was like, oh, this person is losing weight. We need to feed them more. Right, right. So after this observation, starvation diets really kind of got their start. And it wasn't always strictly starvation. You know, some diets were just no carb diets. Some were just certain carbs, like oats only. But in general, they were calorie cutting, with most diets restricting you to

fewer than 500 calories a day. Oh, my. Yeah, that is not a lot. No, you can't live on that long term, but... Exactly. Yeah. I mean, and these starvation diets did seem to work, like, to a degree. I mean, they did nothing at all to cure or even effectively treat the disease, but they did in some cases just, like, slow the progression and help manage these glucose levels. But the stories are horrifying, right? For instance, one woman 43 years old was admitted to the hospital in 1916, weighing 79 pounds or 36 kilograms, and was told to fast. And the last record of this patient showed her weighing 60 pounds, less than 30 kilograms.

before she broke her fasting diet and died shortly after. Oh, my goodness. And another really sad story is of a 12-year-old boy with diabetes, already blind from the disease. He was brought to the hospital so that his food could be closely monitored and his calories even more restricted. His weight dropped to 40 pounds, but the blood glucose didn't seem to be dropping. And so they cut even more and he died of starvation. So these starvation diets, in addition to slowly killing you, were also largely unachievable for most people with diabetes because they required the time and the money to monitor and weigh each individual food item and rest.

And it was just like not a reality. Yeah. So going into the 20th century, the available treatments for diabetes were really more of a choice among evils, right? die of diabetes or of starvation or of opium addiction, just like take your pick. So the need for effective treatment was very obvious and incredibly pressing, even more so since cases seemed to be on the rise. And so far, the only thing that had showed any real promise were the experiments with pancreas extracts that I had mentioned earlier, despite their limited success. In particular, the work of two researchers,

Georg Zulzer from Germany and Nicolet Pellescu from Romania showed that there might be something in it. In 1906 in Berlin, Zulzer had treated some humans with pancreatic extract, but the side effects produced were like really severe, and so we had to stop the project. And 10 years later, in 1916, Paul Escu had succeeded in treating a diabetic dog with a solution of pancreatic extract. Like, it lowered its blood sugar levels. Just, okay. Super cool, promising. But his work was disrupted by World War I when he was called to service.

And by the time he got back, he picked up his work again, but like funds were super limited and he was working almost by himself. So it was just kind of like hard to get. things moving. Yeah. And neither Zulzer or Paulescu would end up getting the recognition they felt they deserved for their role in one of the most monumental and one of the most contentious medical advancements in the 20th century. The discovery of insulin. Insulin. Do that horn again. In fact, like this, the history of this discovery continues to be like a fairly debated topic in medical history, like, who should get credit for it. And so I'm just going to do the best I can to navigate those tensions.

Contentious waters. Yeah. So let's meet one of the central characters of this story, Frederick Banting, born in Ontario, in 1891. Banting began med school just a couple of years before World War I broke out. He joined up. He helped treat combat soldiers. And after the war was over, he tried unsuccessfully to get a permanent position at the Toronto Hospital where he did his residency in orthopedic medicine. So he decided that he was going to move to London, Ontario, and set up a private practice. But it like was really pretty unsuccessful. Like he couldn't quite get it off the ground. And in fact, it seemed like

a lot of areas in his life were just like filled with struggle and strife and like uncertainty. Like he was always on and off again with his fiance. And he seemed like he was always sending out like job applications. He seemed like desperate for a change of scenery or a change of pace in his career. Late one October night in 1920 while trying to fall asleep and what seems like, as he described, stress spiraling. Been there. Yeah, absolutely. His mind drifted to a paper that he had recently read to prep for a lecture that he was

giving on, like, I think, carbohydrate regulation. And this paper, which was written by Moses Barron, discussed the role of the Islets of Langerhont. in the internal secretion of the pancreas and its possible role in diabetes. And he turned the idea over and over in his mind and kept thinking about it and came up with what he thought was the solution to the problem, like a way to isolate that internal pancreatic secretion. And it would involve surgical removal of degenerated pancreas and dogs

and extraction of the secretion from those pancreas. and the next time he was on campus, he brought up the idea to a professor at the university, where he was affiliated, and the professor was like, you know, no, like, sorry, but we just don't have the resources for that. And also there's no one at the university here that, like, knows enough about it to be able to help you. But hang on a second. There happens to be somebody visiting who might. And that somebody turned out to be J.J.R. McLeod, visiting from the University of Toronto, who was an expert in diabetes and carbohydrate metabolism. So Banting met with McLeod. McLeod wasn't like super impressed by Banting, who had a lot of enthusiasm and

confidence, but that confidence wasn't really backed by like a lot of background reading on the subject. He was just like, I'm going to do this and it's going to be great. Oh, mm-hmm. And we've met those. Yeah. And McLeod was like, you know, people have spent their entire careers working on this problem. Do you know about these people? Do you know the work that they've done? But over the conversation, McLeod became more and more convinced. and became eventually interested enough to say, okay, you know what? Sure. Come to the University of Toronto whenever and, you know, we can try to set something up.

But, you know, think carefully about this decision because it would mean giving up your practice and your affiliation here. And also, like, there's kind of a low chance that you would be successful because, you know, this is not a new problem. Like, people have tried this before. So Banting gave it some time and thought and decided to give it a go. But after the other job applications that he had sent out had fallen through and after his fiance had dumped him yet again.

So he was like, you know what? Nothing to lose. I'm getting out of here. So yeah, so he packed up his apartment. He headed to Toronto and got there in April 1921. And apparently he had done no more reading on the subject in the meantime. Oh, my goodness. Not very much because when he met with McLeod, McLeod was like, okay, so I think this is how the experiments should go.

We'll start with this and then we'll do this and then we'll do this. Let's see how we begin. He showed him how to do the procedures, et cetera. And then he was like, also, you know, maybe you should read these papers. read these books get a little more background in it. And then McLeod headed back to Scotland where he was from for the summer break. But before he did that, he gave Banting an undergraduate research assistant named Charles Best to help on the project. And he kind of spent a little bit of time like a month and a half or so kind of walking them through these surgical procedures that they would use on the dogs.

The experimental plan went a little something like this. First, Banting and Best would get practice, Banting on performing the pancreatectomies, and best using the blood and urine tests, and both of them observing what diabetes and dogs look like, like the course of disease. And then Banting would ligate the pancreatic ducts in other dogs, allow them to recover while their pancreas is atrophied, and then re-operate on these dogs,

removing their degenerated pancreases and extracting the internal secretion from them, which he would then inject into the dogs that had been made diabetic from the complete removal of their pancreas. Huh. So it didn't need, like, it was later realized that the atrophy didn't need to happen, but that was what they thought needed to happen first. It's interesting that that part of it worked. I know. Well, you know, and it didn't really work at first.

Things got off to a really rocky start. And it's really sad because a lot of dogs died in the course of this experiment and in many other experiments, especially after the surgeries, which, you know, keep in mind, these were the days pre-anibiotic. Right. So, like, they would just die of sepsis. Yeah, these are not good surgeries. No, no. And in fact, so many dogs died that they began to, like, buy dogs off of the street because they had almost depleted the store of university dogs.

Like, this would not fly nowadays, just FYI. everyone. IA cook would be like, nope. You are getting your research whatever. CRED, yeah. You're not allowed to do research at this university anymore. Or any ever again. Or any, yeah. But finally, finally, after many failures, things began looking up. They were able to successfully extract the secretion from the pancreas, injected into depancreatized diabetic dogs and bring them back from the brink of death and out of a diabetic coma by rapidly dropping their blood sugar. This was like thrilling. Yeah. And Banting was quick to see and believe in the potential of this extract for the treatment of diabetes in humans. But McLeod, who was now

back from his trip, he was urging a bit more caution. He was like, all right, why don't we just try repeating these experiments first, making sure we have, like, good, you know, sample size, and we'll publish the results, see if we can refine the process and make sure that, like, we know exactly what we're doing and that other people can replicate it. Uh-oh. I don't like where this is going by your tone. It's, there's so much drama. It's absurd.

And I won't even go into it all. But so Banting was like not really, he was like, no, I don't want to have to wait for this, but also he didn't really have a lot of like bargaining power. Banting had been working these past few months with like on no salary, on no official position with the university. He was just sort of there. And so he said to McLeod, you know what, you're going to pay me. You're going to give me another assistant to take care of the dogs. And you're going to have repairs done to the operating room.

And McLeod was like, okay. That's actually, you're asking for quite a lot and other research at the university would suffer if, you know, if I were to give all of this to you. And Banting's like, I am going to walk away from this. This is, you know, blah, blah, blah. And so McLeod was like, you know what, okay, fine. You're right. Your work does show promise. Let's keep it going. So this meeting might be where we first see the tension rise between Banting and McLeod. And at this point, Best was already aware of Banting's tendency to be scornful, disparaging, you know, impatient and quick to anger. He had been yelled at at least once for dirty glassware. But this might be, this might have been the first time that McLeod saw it in action.

and this meeting might also have been when the seed of hate was planted in Banting for McLeod. Yeah, it's like really a toxic, it's a whole toxic story and toxic place. Oh my gosh. Yeah. But that seed of hate, it bloomed like wild that December of 1921 at the annual Physiological Society meeting. Banting and Best were due to present their research on the internal secretion of the pancreas, which had progressed since the summer, with the use of pancreas from cal fetuses and then alcohol for extraction from whole fresh pancreas, and things were taking along, and all of their

results were pointing towards successful treatment of diabetes in the animals that they were working with. But at this meeting, during his presentation, Banting, like, told him. totally flubbed it. He was a terrible speaker. He stumbled over the results and it got so bad that McLeod had to keep like stepping in to clarify something or to include a crucial detail that Banting had left out and he answered questions. And then to add, you know, insult to injury, or at least as perceived by Banting, McLeod kept saying we, we extracted this and we injected that. Banting was fuming. There he was. I could only imagine just like standing up there in front of the who's who of diabetes researchers in North America and basically not being able to

string a coherent sentence together while your supervisor is taking what is perceived to be taking all the credit from you. I can 100% imagine that. and it is so cringe. It is really, yeah. And that's, and so Banting, like, he didn't, he wasn't the type to just silently fume. He was like ranting and raving to all of his friends. Like, McLeod is a horrible person.

He's stealing all my results, blah, blah, blah. It, like, really became very bad. And I will say in defense of McLeod, anyone else who worked with him doesn't describe him that way. It seems like Banting was the only one to sort of accuse him of being incredibly territorial or taking credit or stealing credit. So anyway, I don't want to get too much into the whole like, you know. Interlab drama. Right. Yeah. And at this point, it was the entire lab. like McLeod had shifted gears. Like these results were super promising. And so McLeod was like, you know what? Everyone, almost everyone in this lab is going to start working on this pancreas problem.

And he also brought on eventually a visiting biochemist by the name of James Collip, who was added to speed up the extraction and purification process. And so things were happening quickly now with the first human clinical trials. in January of 1922. So just, you know, from April 1921 when Banting arrived to Toronto to the first clinical trial, January of 1922. That's very fast. Too fast. I mean, so the first person to ever receive this pancreatic extract was Leonard Thompson,

a 14-year-old boy who, on admission, weighed only 65 pounds, whose hair was falling out, abdomen distended, breath smelling of acetone, and who was on a diet of 450 calories a day. Oh, my gracious. On January 11th, Leonard received the first injection, which led to a 25% reduction in blood sugar and a slight reduction in urine glucose, but overall the results weren't like super promising, especially since the impurities in the extract led to like an abscess forming at the injection site. Yeah. So the trial was deemed premature, and there was a rush to make a more pure sample, something that Banting took upon himself to make like a competition with Collip, who was like, I don't, this doesn't need to be a competition. Like, can't we just work on this? Yeah. Tensions mounted. Callip won. He, like, found a better purification process. And the new more purified extract was injecting. into Leonard with much better results on January 23rd.

Oh, wow. But a few days before then, before this injection happened, Banting and Collop had gotten into a fight that was at least verbal and possibly physical. Oh, my. Because accounts differ. When Collip announced, he walked into the room and announced that he, A, fine-tuned the Purification Protocol. all, B, was going to keep it a secret from Banting and Best, and not reveal any part of it, and C, that he was going to file a patent on it under his name alone.

Oh, my gracious. And apparently McLeod had okayed all of this. What? So then this led to, I would imagine, a huge yelling match among most, if not all parties, Banting and Bess and McLeod and Callup, I mean, the battle lines were very clearly drawn with those two groups on, you know, Banting a Bess on one side, Collop and McLeod on the other. And then a ceasefire of sorts came in the form of a signed agreement that none of them would patent the process and that they would have to be transparent with each other about research developments.

I mean, they didn't become friends or anything, but, you know, at least like, for now it seemed to have de-escalated. But in any case, the animosity and drama was there to stay. I mean, it wasn't going anywhere. Again, I can't even get into it all. There's a great book I'll recommend that kind of you're just like, what? He said that? Yeah.

And so beginning in the spring of 1922, the lab group began publishing their results. But the important thing is that the popular press picked it up, and that generated a lot of hype among the many people who lived with diabetes. It was in one of these first publications, that was a big comprehensive one from April 1922, that the term insulin was first used. And there's no record as to like why or how they chose that word, but it's based on the Latin root for island referring to the islets of Langarhanes. Okay, okay, okay.

It was clear to everyone in the field that this research marked a new era for diabetes research and treatment. It would certainly be a bad time for things to fall apart, wouldn't it? Oh, Aaron. So Banting had begun to drink heavily and several times decided, you know what, I'm quitting this whole thing. I don't want to be a part of this anymore until best, you know, talk. talked him out of it. And Collip, on the other hand, was having, you know, more like lab-centric problems. He had lost the knack for insulin production. He, like, couldn't, he couldn't figure out. He was like, whatever I was doing before is no longer working for me, and I don't know why.

What? That's weird. It's weird, and it's bad because it led to this insulin famine among the people who had already received injections and, like, were needing those to help regulate their their blood sugar. And then McLeod was simultaneously worried about the lives of the people who needed that insulin. And he was also worried that someone else was going to figure out the production process and patent it. And so even though McLeod, Banting and Best were reluctant to patent it on principle, they wanted to stop other people from creating a monopoly. And so they filed this type of patent that would prevent that from happening. Okay.

McLeod also realized that if they wanted to turn this insulin into an actual medical product that people could reliably get their hands on, they needed to get a pharmaceutical company involved, which is how Eli Lilly came to be so closely associated with insulin. It was someone from Eli Lilly at that very first meeting and they were like working very closely with the Toronto team to get like the sole ability or license to try to manufacture this this new insulin. Yeah. But, you know, the drama of discovery, the incredible tension among the researchers, the

difficulties in streamlining or fine-tuning the production process, all of these problems were overshadowed by the absolutely enormous. enormous impact that insulin was having on the lives of people with diabetes. A lot of accounts at the time describe the drug, describe insulin as miraculous, and it's kind of hard to disagree with that. Yeah. Like a 16-year-old boy brought out of a diabetic coma from an insulin injection the first time that had ever happened.

Yeah. A bedridden child jumping around the room hours after being given insulin. Perhaps the most famous patient from the time was Elizabeth Hughes, who was daughter of the U.S. Secretary of State, who kept journals of her life pre and post insulin. And at the time of her first insulin shot, the 15-year-old Elizabeth weighed less than 50 pounds. Oh, my. That's like 22 kilograms. It's, yeah. And she was close to death.

A few weeks after receiving her first. first insulin shot, she gained 10 pounds. Wow. And a lot of health problems resolved for her. And she went on to live like a healthy and relatively long life. And there were a million more stories just like these. Insulin saved and continues to save so very many people from what was absolutely a death sentence. Yeah. It kind of reminds me a lot of like the stories of when antibiotics were first developed and first introduced, and it was like, it was miraculous. It was coming back from the brink of death. Right. It must have been, like, unbelievable to witness. So who was responsible for insulin's development and who gets the credit? And are the answers to those questions the same?

Well, it depends on who you ask, right? If you ask Banting, it was Banting with a little help from best. If you ask McLeod, it was McLeod, Banting, and Collop. If you ask Paulescu, it was Pauluscue. And if you ask the Nobel Prize Committee, it was Banting and MacLeod. So in 1923, the two were awarded the Nobel Prize. Banting was only 32 at the time. Oh, gosh. At the time, I think he was the youngest for like physiology and medicine or whatever the grouping was at the time. But Banting was furious. He could not believe that his and McLeod's name were both on the prize. Oh my goodness. He believed it should have been him and best. And so at first, he was like, you know what, I'm going to refuse this prize. I don't want anything to do with it.

And then eventually he was like, actually, what I'm going to do is I'm going to split it with best and that's what he did and McLeod in turn decided that he was going to split it with callup. Okay. I don't know who deserves it. Honestly, I mean, does Pauluskew deserve some credit? Absolutely. Soul credit?

Probably not. Would Banting have gotten there without McLeod or without Collip? Probably not. All these tensions and credit debates aside, though, the important thing is that insulin was now available. And just in the way that blood transfusions for hemophilia turned that disease from an acute disease to a chronic one, insulin prolonged the lives of those with diabetes, but it was also not a cure. And the long-term consequences of diabetes, particularly type 1, were emerging,

such as kidney disease and retinopathy and all the ones that you've already discussed in the biology. So I'm not going to go through these next things in detail, but following the discovery and production of insulin, a lot of other important developments occurred. Frederick Sanger discovered that insulin was a protein and described its structure, for which he was awarded a Nobel Prize in 1958, his first of two. Yep. And Dorothy Hodgkin, whose name you might remember from our antibiotics episode and our radiation episodes. Yeah.

So she used X-ray crystallography to work out the 3D structure of insulin. A lot of research focused on treatments for the long-term consequences of diabetes, such as kidney disease and ulcers and kidney transplants, and some really important work was done by Priscilla White on reducing perinatal mortality in people with diabetes, by introducing sex hormones as treatment, which hugely increased survival of the babies. And there was yet another Nobel Prize for diabetes research,

co-awarded to Rosalind Yalo in 1977 for developing the radioimmune assay to measure the concentration of hormones like insulin, vitamins, viruses, enzymes, and lots more stuff in humans. Genetic engineering allowed for the mass production of biosynthetic insulin, and I think we might have touched on that briefly in our E. coli episode. It was basically like engineering E. coli to just like pump out insulin. A ton of insulin. Okay. That sounds vaguely familiar.

And then the threat of bovine-spongeform encephalopathy in bovine-derived insulin and kind of pushed for like this switch towards human insulin. And then insulin pumps were developed and since the 1970s they've shrunk in size considerably and increased their capabilities considerably. In 1979, diabetes was officially divided in. into two types. Insulin-dependent diabetes maledus and non-insulin-dependent diabetes meletus, or type 1 and type 2, as they were called, beginning in 1995. And in the late 1970s is also when gestational diabetes and what was called maturity-onset diabetes of the

young were also recognized. There have been too many developments to even mention. This year, 2021, marks the 100-year anniversary of insulin, and over that time, diabetes has undergone a huge transformation in terms of our understanding of the disease and our ability to treat it. But the story isn't over, because alongside these medical developments, diabetes was going through another kind of transformation in the 20th century, a social. transformation, if you will. Okay. Diabetes part two. I promise this is a lot shorter. So I know I've been talking for ages. I've been enjoying it. Okay, good. I hope that remains true. So I can only

speak for the U.S. or my experience in the U.S., but in many things that I've read or seen on TV or I've heard in the classroom, there's this sense that diabetes, type 2 in particular, is a personal choice with this tinge of morality surrounding it. Similar in some ways to how STIs are talked about. Like, oh, you did these things. So like, what do you expect? You deserve this. These are the consequences for your actions. And this, I think, reflects a huge problem, not just in showing like a complete absence of empathy, but also in revealing a general lack of understanding about the multifaceted nature of this disease and refusing to acknowledge the institutional drivers that increase the risk of diabetes. Yeah. So when I was prepping for this episode, I read a book

called Diabetes, A History of Race and Disease by Arlene Marcia Tuchman, where I learned that it's kind of like always been this way. Like there's always been sort of this, oh, well, these are the consequences of your actions. Or like, oh, this is a personal disease. Like, this is something that you did, right? It's always been very much like a blame the individual or the identity of the individual kind of a disease with a particular trait or group at fault being the main thing that has changed over the decades. I had no idea before researching this episode, but it turns out that diabetes started out as a, quote, like, Jewish disease.

In the late 1800s, when the visibility of diabetes and other chronic diseases was increasing as infectious diseases declined, diabetes was literally given the name, quote, the Jewish disease in Europe. because of the supposed high prevalence of the disease among Jewish people. And the reason for this high prevalence varied based on the individual views of the person you asked or the person who was writing this article. It could be because of the long years of cruel persecution faced by Jewish people that led to this high levels of stress,

or it was because they overindulged and ate rich foods, or maybe it's because they had a, quote, nervous disposition. Or it was just a way of saying that this disease had, you know, foreign roots since the immigration of Jewish people from Eastern Europe was really high during this period. But whatever the perceived reason or stated reason at the time, this association grew global and it became entrenched in medical literature and in the minds of practicing doctors for decades. So like from the late 1800s to like a few decades into the 20th century.

Huh. Yeah. Was there actually an association? I mean, without any quality statistics from the time, we can't say for sure, but it seems unlikely. Yeah. It seems that it was more bad statistics turned into common knowledge and then like helped along by confirmation bias. definitely a citation needed moment. And that was a big problem.

It just kept being repeated in the literature without any citation or citing someone who just said, it's really highly prevalent in Jewish people. And even if there were numbers in these articles, was the categorization of Jewish and non-Jewish even helpful? Was it meaningful? Both groups were very heterogeneous. So drawing those lines was really a way of kind of like pushing a certain narrative. The way that you draw the lines is definitely like you have a bit of forethought about what you,

what statements you want to make when the numbers all kind of fall out, right? Like what's important to you about those divisions? Right. And often, you know, as it is now, but as it was back then, you know, those divisions were a way of saying that something about your race or your background or your culture made you more likely to have this disease. And we see this theme, you know, race presented as an explanation for disease again and again in the history of diabetes with black Americans and the Native Americans and Mexican Americans and so on.

And certainly the use of racial categories and epidemiological studies can be very helpful, but they're helpful for confronting and trying to understand institutional racism and inequalities in health care or access, not to further the myth of race as a biological construct. And yet, Aaron. And yet, Aaron. Okay, so from its reputation as a, you know, quote, Jewish disease in the late 1800s, diabetes slowly began to be viewed as a disease of moral failing, especially in the years following a World War I, which were a period of economic growth and increase in consumables and big cultural shifts, leading to culturally conservative people shouting that like the increasing rates of diabetes were a sign of moral decay of this like

gluttonous overindulgent society that has no self-control. The shifting from a Jewish disease to like a more general sign of, you know, moral decay or whatever also happened as more studies were done to show that there wasn't actually. much of a difference in terms of stats. Right. And this moral failing or overindulgence or just the rate of diabetes, it had a class structure to it. Diabetes had shifted its reputation to one of middle and upper class and generally white people.

Huh. In fact, it was thought and published in medical journals that black people were immune to diabetes. What? It was literally in, in medical journals. medical journals, well, they are known to be immune. Same was said about Native Americans also. So why did people think they were immune to diabetes? I don't know, Erin, why? I mean, we don't know for sure, but we can speculate. It's likely that it had, you know, a large part to do with a lack of access to primary care physician or hospitals. So, like, doctor

just simply weren't seeing diabetes in black people because they weren't treating black people. And it's also possible that doctors simply were like, well, I'm not going to test the urine of a black person because they're immune. I read that in literature. So there's no point in even testing you for diabetes. But the reasons for this lower prevalence were given or written about in racist terms, right? Black people didn't have the, quote, like, nervous strain or, quote, mental strength for diabetes. What? I know. It is... What does that even mean? Basically, what I gather from this is that people wanted diabetes to mean whatever they wanted it to mean. Yeah. They couldn't find a cause. They couldn't explain why it happened. And so then they looked around and thought, okay, what is the

narrative I want to push. Yeah. It all had to do with just like individual biases, societal biases, and, you know, racist ideals. It's, yeah. That's so weird, Aaron. It is, yeah, it's all about the narrative. But then here comes another shift, right? Another transformation of diabetes. So when actual statistics introduced in the 1920s showed that rates of diabetes didn't differ much between black and white Americans. But do you know what did? Mortality rates from diabetes. Mm-hmm.

Mm-hmm. And another factor that contributed to the overall growing visibility of diabetes among black Americans was the increase in black medical doctors who wanted to help improve the health of the communities that they served. And what many of these doctors saw was also reflected in the stats from the time, and also from today, that as poverty increased, the rates of diabetes rose, and that diabetes in general seemed to be on the rise. In the 1930s, an estimated half a million to two million people in the U.S. were living with the disease, and it rose to be the ninth-lead

and cause of death in the U.S. in 1936, which is up from the 27th in 1890. The development of insulin in the early 1920s helped out a bit with like the management of diabetes, but a lifetime of injections was still costly and long-term effects were still present. And also, since this is an episode of TPWKY, I have to mention eugenics. So here we go. Eugenesis, as you might guess, were not a fan of insulin, saying that it would increase the numbers of unfit people in society.

We saw it coming, Aaron. I know. It still hurts every time. Every time. But a huge problem with the eugenesis arguments, you know, besides the fact that they're terrible and they were making judgments on who should or should not reproduce, was that no one could predict who would get diabetes. That still, you know, is true today.

The how of diabetes was beginning. to be worked out, but the why had not yet been answered and still isn't really fully answerable. We'll get back to it, Aaron. Well, why did some people get it and others not? Why were we seeing an increase in the U.S.? In 1962, James Neal thought he might have the answer. Have you heard of the thrifty genotype? Yeah. Okay. It's basically. Basically this idea proposed by Neal that this thrifty genotype would have helped early humans live through periods of unpredictable food availability.

So you would store more fat in times of plenty to prepare for times of famine. But in the U.S. and other developed countries where diabetes was on the rise, there weren't really these times of famine. And so the thrifty genotype went from good to bad. It began to backfire. And at first, this thrifty genotype hypothesis was just used to explain a global growth in diabetes prevalence. But with recent reports showing a disproportionately high rate of diabetes among some Native American groups, it became used in this colonial narrative of, quote, primitive and, quote, advanced societies.

Ew. And in this narrative, some Native American groups were said to be more. more prone to develop diabetes because they were, quote, primitive people who were rushed into, quote, you know, modern living conditions and they were unequipped to deal with the diet and lifestyle. That is such a mischaracterization of, yeah, I can't. Yeah, yeah. I mean, it's quite the turn from diabetes as a mark of civilized society that was popular earlier in the century.

Yeah. And the thrifty genotype hypothesis is not well supported at all, I should note, despite it continuing to be pushed by some people, Jared Diamond. But by couching the high prevalence of diabetes in certain Native American groups in biological or genetic terms or concepts, it made and continues to make it possible for the government to ignore their own role in the the cycle of poverty, in the impact of displacement, genocide, and federal policies that lead to higher rates of disease, not just diabetes. Speaking of the federal government, in the 1980s, a nationwide study called the Heckler Report investigated racial and ethnic health disparities in the U.S. And what they found was that diabetes, specifically type 2, and mortality from diabetes,

occurred at disproportionately high rates among non-white people. The report framed diabetes as a, quote, disease of minority groups. It barely acknowledged the role that poverty played, but rather it emphasized the racial and ethnicity differences and to some degree sex differences, this continued the long tradition of attributing diabetes to a moral failing

or personal quality or to a certain racial or ethnic background, all the while ignoring the role that poverty and other factors, like food deserts, like the ability to be active, that all of these things can play. Yeah. Diabetes is such a nuanced disease,

Yeah. But it seems as though somehow we struggle still to make sense of that nuance and present it in a way that is like, oh, okay, there are multiple parts to this story. So I've rambled on and on. And Aaron, why don't you bring me up to speed on what's happening with diabetes today? Oh, I'll do my best, Erin. Let's take a quick break first. Why don't we just start straight in with the numbers? We'll get right to it.

And then we'll go through advances in treatment and then hopefully answer a little bit more of your question of the why and how. Okay. Oh, good. So, according to the International Diabetes Federation in 2019, diabetes, diabetes, and this is all types of diabetes, of which generally 90% or so are type 2 and 5 to 10% type 1, and then gestational and the other types of diabetes account for the other percentages. So in 2019, diabetes caused 4.2 million deaths worldwide.

And 463 million adults, this is just adults, between age 20 and 79, were estimated to be living with diabetes. And that number is likely to rise to up to 700 million by 2045 because both type 1 and type 2 diabetes have been increasing. Right. And it gets a little worse. the true disease burden, especially for type 2 diabetes, is likely a gross underestimation because one in three people who have diabetes are underdiagnosed. That's over 200 million people. Whoa.

Yeah. And then if you also account for all of the people who have impaired fasting glucose or what sometimes is called pre-diabetes, the vast majority of those people have no idea that that's what's happening inside of their bodies. Hmm. Okay. And a good proportion of those people may go on to develop type 2 diabetes. A little worse than that. While there's a lot of variation in both incidents and prevalence of both types of diabetes across the globe, like different prevalences in different areas,

overall, more than 80% of people currently living with type 2 diabetes are currently living in low or middle-income countries, which especially as we talk about the new developments in treatment poses additional challenges, because most of these are, unsurprisingly, very expensive. And there are, of course, major economic and social hurdles for people living with diabetes in low- and middle-income countries, but also across the globe, including here in the U.S. For example, insulin prices in the U.S. are truly an abomination. In 2018, a unit of insulin was $98.70 in the U.S. compared to $8.81 in 32 other countries.

And while diabetes is certainly not exclusively a disease of low income, when you consider not only the price of insulin, insulin, but the price, like I already said, of so many of the newer and in some cases better drugs for type 2 diabetes that are also incredibly expensive, diabetes certainly contributes to the cycle of poverty across the globe. So that's all the bad news, and I know there's a lot of it, but there's at least some good news on the horizon. I usually talk about whatever's going on in terms of research. And a lot of times I feel like I'm like, oh, there's not much going on and it's like depressing.

But today I don't have a lot of very specific things to go over. But that's because there is so much research going on in terms of diabetes that there's simply too much ground to cover, which is amazing. That means that there's so many people working on so many different aspects of this in terms of new treatments when we look at type 1 diabetes in general and i apologize if there's even newer things that i have missed but in general the treatment is still just insulin and while that sounds simple it's a very complex to kind of get regimens and know how much you have to give etc but some incredible advancements for type 1 diabetes or insulin dependent type 2 diabetes

is the development of continuous glucose monitors. And like you mentioned, increasingly small and easy to use insulin pumps that can keep much tighter control of that glucose, which can then prevent the development of complications. So that's incredible. When it comes to type 2 diabetes, oh, my gracious, the number of new drugs, I think there's a new one every day. And a lot of them, like we kind of touched on a bit before, are touching on different mechanisms of diabetes control. So previously, things were just working on increasing the amount of insulin that people secrete. But now, because we know that insulin resistance is a big component, there's other types of treatments that are targeting tissues to make them more susceptible to the effects. There's a lot of really cool stuff going on with type 2 diabetes treatment.

Yeah. That's interesting. It's very, very cool. There's also so much work being done to better understand the genetic components of both types of diabetes. So I want to kind of stick with that for just a moment, and then we'll wrap up. So both type 1 and type 2 diabetes have genetic links, but it's not like any of the genetic disorders that we've covered in the past where it's like a single gene. It's many different genes. and it's not a strong genetic component for either type 2 or type 1 diabetes. But one of the biggest questions, Erin, that you kept asking me was the why, the how,

especially when it comes to type 2 diabetes. And so like I mentioned, both type 1 and type 2 diabetes have a genetic component. Type 2 diabetes has a much stronger genetic component, meaning if you have a first-degree relative with type 2 diabetes, you are much more likely to develop type 2 diabetes yourself than you are if you had someone with type 1 diabetes to develop type 1. That makes sense? Uh-huh, okay. So there's a much stronger genetic component to type 2 diabetes.

But it's not a single gene. It's very multivariate. And just like with type 1 diabetes, there's also a huge amount of environmental components that go into the development of type 2 diabetes. And some of these are what are often called modifiable risk factors. And these are factors in the environment that can change and that can lead to risk of diabetes. The things that we know that are the most strongly associated are sedentary lifestyle, which essentially just means not getting a lot of physical activity throughout the day.

Another is diet. So having a diet that's really high in. sugars that are like the kind that you find in soda is really strongly associated with type two diabetes. And then the one that's cited the most frequently is obesity. So BMI is the indicator that we use to classify obesity. And obesity in the U.S. at least is considered a disease, which is then also considered a risk factor for diabetes among other things, type 2 diabetes specifically. And BMI is not just in my opinion, but also in my opinion, not a good indicator of health. Not only does BMI not take into account things like muscle mass or the

distribution of adipose tissue, whether it's central and around your organs versus on your legs or arms, etc. BMI also ignores so many of the social determinants of health that play into the overall risks of diabetes and so many other diseases. So BMI and obesity in general, it's not a good indicator. But in the literature, it is considered a risk factor for type 2 diabetes. Mechanistically, what is it about those things that causes insulin resistance and like a faulty production of insulin? Yeah. And that is the question that we still absolutely do not know the answer to. But here's something exciting, and it still doesn't address the question of why those risk factors then lead to this, but I found a couple of articles that are really

promising on the underlying mechanism before you even get to insulin resistance. And that is dysfunction in the brain itself. Huh. So dysfunction in the hypothalamus that was treated with a single dose of something called fibroblast growth factor resulted in mice in sustained diabetes remission, a single dose. So these papers were basically suggesting that what happens, for whatever reason, from this genetic susceptibility and these environmental factors, is that the effect on the hypothalamus in your brain is to increase your body's set point for what is an okay level of glucose. that is super interesting.

Isn't it fascinating? And so then by giving this dose of this FGF1, what they were doing was lowering back that set point to something more like 120 instead of like 200 or whatever. So then your pancreas doesn't have to compensate to try and increase insulin because your body, your brain is telling your body, it's okay to let my blood glucose get this high. and your pancreas is like, no, it's not, it's really not. Again, that still doesn't address this underlying question, but it does give us a much better target for the like mechanistic cause. Did you come across anything about epigenetics? I mean, epigenetics is a huge part of this.

Right. And that's, but no, I didn't read any papers about it. And so I don't know like what those mechanisms are. But with any of these like polygenic and gene and environment things, I think epigenetics plays a huge role. But I think, too, Aaron, getting back to what you were saying in the last part of your history section is it's so important, especially in a disease like diabetes when we're talking about things like these modifiable risk factors, to not lose sight of the environment that we are in and the structures of government of our society. that force us into this environment where we can't do physical activity because we're sitting at a desk at our jobs for 10 hours a day and then we're driving in our car an hour each way to work and then we can't afford to buy fresh leafy greens because they go bad in 20 minutes in your fridge and also they don't

taste that good like there are so many things that play into this it's not an individual choice It's so much bigger than that. Yeah, it's a really multifaceted. Yeah. Like issue and discussion and... And again, BMI is a bad indicator. Hoof, boy. Don't get me started on that one.

So that is diabetes. In brief. In brief. You know, short and sweet. We kept it nice, long and sweet. Yeah. Sources? So I will mention, I basically relied on three books. The first one is the Discovery of Insulin by Michael Bliss. I feel like it's a really well-researched and even-handed look at, you know, credit for the discovery of insulin. And apparently there's also a mini-series about this story called Glory Enough for All. I think it's on YouTube. And then I also read, as I mentioned earlier, diabetes. A History of Race and Disease by Arlene Marsha Tuckman. And finally, Diabetes, the Biography by Robert Tattersall.

Awesome. The vast majority of my biology for the first time in forever came from a single textbook. So big shout out to the principles of diabetes, Meletus, by Peretsky, editor. And then a few other papers here and there for a little bit of specifics. And if you're interested in that brain glucose. research. I have two papers, one from nature communications 2020 and another from diabetes. That was from 2019. They're both really interesting, but very detailed papers. And we'll post all of these

sources for this episode and every episode on our website. This podcast will kill you.com. Thank you again so much, Carla, for coming on and chatting with us. We really appreciate it. Yeah, thank you so much. And thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to the Exactly Right Network, of whom we are very proud to be a part. And thank you to you, listeners, for listening to this very long episode. This is a real doozy. And what it is.

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