#41 - Jake Kushner, M.D.: How to thrive with type 1 diabetes and how everyone can benefit from the valuable insights

Foreign. Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics@peterattiamd.com. Hey everybody. Welcome to this week's episode of the Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. 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Again, the podcast will remain free to all, but my hope is that many of you will find enough value in 1, the podcast itself, and 2 the additional content, exclusive for members, to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Jake Kushner, a close friend and a pediatric endocrinologist who specializes in helping manage people with type 1 diabetes. In this episode, we go into great detail about type 1 diabetes. Probably the biggest takeaway from this episode is that diet can help people not only with type 2 diabetes, but also type 1. Jake discusses some of the recent findings in an approach that that one of the pioneers in this field, Dr. Richard Bernstein, championed for several decades now, managing carbohydrates and protein to manage insulin and glucose. And if you're thinking, well, I don't have type 1 diabetes, why does this matter to me? The answer is anybody with a pancreas is going to benefit from this, and obviously those without a pancreas, which is effectively what is happening in type 1 diabetes. We also discussed why many patients who control their blood sugar with high Amounts of exogenous insulin are at substantially higher risk than. Than people who can control their blood sugar at lower levels of insulin. This concept also has implications for everyone else, as I said, because the word exogenous and endogenous can be interchanged quite easily when it comes to insulin. We cover some of the basics, the history, the increasing prevalence of type 1 diabetes, and more importantly, what we can do to help kids with this disease and their families and the non diabetics out there learn from them and their disease. So, without further delay, here is my conversation with Jake Kushner. Hey, Jake, thanks for. Thanks for coming over, man.

Hey, Peter, thanks for having me. It's a pleasure.

What do you think's the probability we will get through this discussion today without one of my kids barreling into this room?

Absolutely zero. Especially given that I met both of them and they're incredibly rambunctious and cute.

Well, you met two boys, but there's a girl, too.

Okay.

Oops. She's much more well behaved. So you're in town. I guess we can't talk about it. It's black ops mission, right?

No, it's actually. So I'm an advisory council for Sanofi, and I've been an advisor about this drug, Sotagliflozin, which is part of a new class of drugs that will hopefully benefit people with type 1 diabetes. These adjuvant therapies, molecules that you take in addition to insulin. And I've been involved in this program now for close to seven years.

And I know, off mic, we've spoken a little bit about some of those compounds. They're super interesting, not just for type 1 diabetes, but potentially type 2 diabetes. And frankly, if you subscribe to the idea that lower levels of glucose and insulin are just better overall, there may even be other applications. So before we get into that, we met. It's been three or four years now, right? We met in Houston over dinner one night. And I gave you credit for this recently on a podcast that hasn't yet released, but it will release. It was actually you who first told me about cgm, although it was officially Kevin Sayre at Dexcom, that got me fully hooked. So whenever I'm talking to somebody and they ask me about a question that has to do with type 1 diabetes, I generally say, like, I know very little about this condition, but you should meet Jay Kushner, because not only does he get it, but I think his outcomes are pretty unique. I think we're seeing more people move towards the realization that you and people who think like you have. So you're a pediatric endocrinologist. Did you always know you wanted to do that?

Well, I was trying to decide in between being a pediatrician and being a molecular biologist, and my parents are basic scientists. And there was a well worn path in between molecular biology and endocrinologies. That was a really typical thing back in the mid-80s. And I thought I would do that. And the classical path as an endocrinologist is to go and find a rare disorder and discover the molecular basis for it and find some unique product that you could then replace and provide it, and then you're good to go. And there's a lot of endocrinologists who made quite a bit of hay on that paradigm. And so I was also interested in pediatrics. I was trying to decide between all these things when I was an undergraduate at Berkeley and working pretty much continuously in basic science research labs all the way through Berkeley and then for several years afterwards as a research technician, first at UCSF and then Oregon. So I apply to medical school and I get in and I think I'm going to be a pediatrician. And my mother was greatly disappointed that I didn't become a basic scientist. She. She viewed science as much more compelling than becoming a pediatrician or any doctor for that matter.

Right. I mean, there could be no greater letdown to scientific parents that you would choose something as low as medicine.

And I was literally the only kid in medical school whose mother was disappointed that I didn't end up going to graduate school.

If it makes you feel any better, my dad was very disappointed that I went to medical school, too.

I found myself there. I thought I was going to be a pediatrician. I did my clinical rotations, and it totally reinforced it. And I just love being on the wards and interacting with kids. And then ended up as a pediatric resident at Brown and had again, I had worked in molecular endocrinology as a researcher before I went to medical school and was enamored by endocrinology in general. And I applied and got into this program at Boston Children's. So there I was in this incredibly busy, rigorous, unbelievably complicated place. And that's when this crazy thing happened in my life. And so I thought I was going to find some esoteric metabolic disease to work on.

And you were at the right place to do it, because for the folks listening who might not know this, there are probably, what, four major pediatric centers in North America. Boston Children's, obviously in Boston. Sickkids in Toronto, Chop in Philly and maybe Texas Children's. Would that be in the top four?

Yeah. And ucsf. That's right.

Would UCSF actually make the top five at the time?

It did.

Okay.

Incredibly strong. So I sort of thought I would do this and I'd find some esoteric disease like maybe work on calcium or, you know. But as a first year endocrine fellow, we're running around an incredibly busy service and we're interacting with families of children who are newly diagnosed. And it's such a compelling. With type 1 diabetes, and it's so compelling. So we would take call, the ER would call us, oh, there's a child who's been diagnosed. We come in the next morning and meet these families. And, you know, there's a tearful, exhausted, overwhelmed mother. There's a kid who literally looks like she's been like shot out of a cannon, you know, with multiple IVs and scars in her, in her arms from blown IVs. And we have to try to work through this idea that they were going to be insulin dependent for life. And I just thought, wow, this is really an amazing and challenging problem. And it has so many aspects of medicine that I appreciate as most importantly human elements. But there's also basic science.

The diagnosis is. I mean, I had one experience with this before I got to medical school, which was in college. I had a really good friend who, I guess I won't use her name just in case I need to protect her identity. And she was amazing. She was my lab partner. We're just great, great buddies. She was a stud athlete. She was in the rowing team. She was like the perfect physical specimen of. And we used to sit together and we were in two classes together. And she was like maybe four or five months into that school year, and she couldn't stay awake anymore. She was like falling asleep in class constantly. And I remember sort of nudging her and being like, hey, you're burning it too much. Like the practices are killing you and the labs and blah, blah, blah, blah, like, you got to get this shit under control. And she's like, no, no, I'm fine, I'm fine, I'm fine. She just couldn't stay awake to save her life. And she was losing weight like crazy. And she was lean to begin with, so she was probably 6ft tall and might have weighed 140 was her fighting weight. And. And she was now down to 125 or something like that. And of course she was going to the bathroom all the time. And of course I'M just a dumb engineer. I don't know anything. I don't realize. This is such an obvious sign of somebody who's going to be diagnosed. Yeah.

In a medical school and you can't diagnose, but it's really difficult for everybody.

Oh, this was an undergrad. Oh, yeah. This is before I even knew I wanted to go into medicine. But, yeah, sure enough, she comes back one day and she's like, oh, my God, you're not going to believe this. I finally went to the doctor and all of a sudden, for the rest of school, she takes insulin and for.

The rest of her life. And these are previously healthy people, they're cruising around, living their lives. There's nothing obvious that contributes to their risk. And then they start drinking a lot and peeing a lot and they lose weight and they essentially are in a state of profound catabolism and their bodies waste away because insulin is such a really pivotal signal for directionality on metabolism. And they decide to break it down. And it's amazing. It beguiles everyone who's up there close. There are so many misdiagnoses around type 1 diabetes. About 30% of children still present with DKA. That is to say, they've had prolonged illness and no one's thought that they could actually be quite ill.

So when, to be clear, when they present with diabetic ketoacidosis, it means that they have somehow managed to slip through the cracks. Nobody's figured out that their glucose level is through the roof or that they're becoming acidotic or any of these other things. And what actually brings them into the hospital is a septic like situation where their blood pressure is falling and they're becoming unresponsive.

Yeah, they hit the metabolic wall and at that point they're only on this earth for a matter of days or a week or two without insulin. And it's quite common for very young children to present in dka. It's less common in older people. They typically have more compensatory reserve, so they have more. The autoimmunity proceeds at a slower rate as you get older. And so the diagnosis becomes more and more confusing the older the onset of the disease. And this phenomenon actually progresses into adulthood to the point where there are people our age who are diagnosed with diabetes, not otherwise specified, who think they have type 2 and they're skinny, but in fact have cryptic type 1 diabetes. They probably have autoimmune antibodies and they have some degree of a loss of beta cells. And this phenomenon explains some of the adult onset diabetes that you just don't quite understand. How is this person diabetic?

And so fast forward a few years from where I am and I want to come back to where you were. But by the time I'm in medical school, I had only been exposed to people who had type 1 diabetes, which is ironic given the prevalence difference between type one and type two. And I remember in a pathology class in my first year, they said, well, you know, I forget what the number was at the time, but they said about 95% of the cases of diabetes are what we call type 2 or adult onset diabetes. And I remember thinking to myself, the professor must have made a mistake. I've never seen this type 2 diabetes thing they talk about, but I've seen a lot of people, not just that friend in school, but I went on to see other people and knew of other people, though I didn't watch them through the diagnosis. So what is the prevalence today notwithstanding this late onset type 1 diabetes that we'll come and talk about later? But just directionally, how many people in the United states have type one versus type two or indeterminate?

Okay, so type one is approximately one in 300 people. And the typical age of onset is around nine. And they live into adulthood and many survive into their 80s or even 90s. They have, of course, reduced survival because of complications, but it's an incredibly common illness. It's the most common life threatening medication requiring illness of childhood.

Yeah. Which is amazing when you go back to where you were at Boston Children's Hospital. I'm sure for any pediatric endocrinologist to be working on glycogen storage diseases or inborn errors of metabolism is interesting intellectually. But the scale upon which those diseases afflict children is trivial compared to what you just described.

And when you're working in a fancy medical school, it's quite sort of tempting to focus on a rare, unique condition that most people don't get a lot of exposure to and sort of bypass the really common things. But for me, type 1 diabetes was the elephant in the room. It was just so compelling. And I ended up being the first clinical fellow at Boston Children's in 10 years to go into type 1 diabetes.

Were any of your mentors there disappointed in the way that your mom was. That you were sort of, I don't want to say slumming it, because I don't mean to suggest that that's what it was, but. But that you were stepping off the pedestal of the esteemed academic institution?

No, I Ended up working on type 1 diabetes at the Johnson Diabetes center, which was an amazing place. And there was also in Boston, also in Boston. There was a long august tradition of academics there. They were a little surprised that I was interested in going after such a tough problem. And again, clinically, type 1 diabetes is an immense problem, as we'll get into, because the clinical treatments are just so difficult and ineffective and variable in their response.

So let's talk a little bit about the pathophysiology of this. Presumably people listening to this who already know everything about it and want to get to the fun stuff will skip this. We'll timestamp it so they can jump ahead. But I think it is worth understanding because there's definitely some confusion. You obviously alluded to the fact that this has an autoimmune component, if not the main component. So what, based on everything we know today is the pathophysiology of this condition?

Okay. Well, I guess we could say just from a very high level, there are clearly genetic as well as environmental contributors. And so we know that it runs in families, and we know that certain regions or certain behaviors predispose. But if you actually get down to the molecular pathophysiology, what you see is that it's an autoimmune condition largely driven by T cells, but there is also a contribution of B cells. And because of that, you can detect antibodies in the serum that indicate autoimmunity. And so we generally believe what happens is by some combination of bad luck and possibly genetics and possibly the foods you eat. To a very, very modest degree, this stochastic phenomenon begins to move forward, whereby the beta cell, which secretes insulin, begins to dump off antigens, and the antigens begin to provoke the immune system locally, and some of those immune cells start to destroy beta cells and dump out more antigens.

So let me take a step back for the listener. The pancreas, of course, is this gland.

Yeah. Thank you.

No, no, no, that's fine. The pancreas is this gland that sits in the retroperitoneum. So it's not in the abdomen proper, but it's behind the stomach. And about 95% of the pancreas by mass, serves this exocrine function, which is. It's mostly there for local digestion. It puts enzymes and into the biliary stream that ultimately aid in the proximate digestion of things come out of the stomach. However, about 5% of the pancreas by mass, including these cells called beta cells. But presumably you'll tell us A little bit about alpha and delta cells. It's an endocrine organ versus an exocrine organ, which means it's secreting systemic hormones into the system. So I remember learning that in medical school and being surprised because I'd heard so much about beta cells. And I was like, wait, they only make up 5% of this pancreas? Like, they're a relatively small contribution to this enormous organ. Right?

And essentially insulin is only made there, except perhaps in tiny quantities in the brain. And so, yes, these islands of cells, these islets of Langerhans, exist floating in a sea of the acinar or exocrine component. And they make insulin uniquely unlike any other tissue. And perhaps because they make these unique antigens or these unique cellular products like insulin and some of the other apparatus that are required for glucose stimulated insulin secretion, when they begin to dump off their antigens and provoke autoimmunity, you can get this sort of death spiral where ultimately the end result is a progressive autoimmunity where you lose beta cells over time. And I don't think that there's any one single, for instance, virus that can be conclusively ascribed to autoimmunity. And type 1 diabetes, it's clearly not related to, directly related to your BMI or your body mass index or your body weight, though it's certainly a contributor. And also genetics are which way does.

It seem to contribute high or low in populations?

Again, it doesn't hold up in individuals very well. But in populations, the heavier you are, the more likely you are to have type 1, which implies either that the work of the beta cells contributing to the autoimmunity, or alternatively, the work of the beta cell and the relative beta cell insufficiency reveals this autoimmunity that otherwise would have been cryptic.

We've seen a rise in the incidence and of course then the prevalence of type 2 diabetes, that's very difficult to ignore. And I've written about that in other places. And you can chase that all the way back to the late 1800s. And it tracks pretty well what has been the relative change in the incidence of type 1 diabetes.

So it's doubled since 1960 and it appears to be continuing to increase. And so one possibility is that there are these environmental factors that are increasing, for instance, obesity, alternatively, there could be viruses or other things that we're exposed to. And another possibility is that we're simply better at diagnosing it. So we know for a fact that some infants that are diagnosed now with new onset diabetes would have been the kids who you thought had died of sepsis back when you were in medical school. So we have a greater awareness that this autoimmunity can happen to kids as early as five or six months of life. And at that point they don't present with the classical signs and symptoms. It's really incredibly aggressive. They look like they have gastroenteritis and weight loss. And if nobody bothers to check a serum glucose, you might never know that they in fact have life threatening diabetic ketoacidosis and new onset type 1 diabetes. It's a disaster.

I suspect it was because I knew we were going to be speaking today. But last night when I was putting my littlest guy to bed, who's about 16, 17 months old, I remember I was looking at him and I was playing with him and I'm biased, so I think he's as cute as all hell. And I remember thinking, what would happen if this guy got type 1 diabetes? Like, how would we figure it out? Like, how long would it take us to figure out, oh my God, check his glucose? And it scared me, actually, because it's like, I think about this stuff night and day and I realized it would easily escape me for a long time. And to your point, they don't have the reserve. They don't have the physiologic reserve, which is just doctor speak for they don't have the buffer between life and death that, you know, you or I would.

Have, and actually might have much more.

Aggressive autoimmunity, meaning it comes on quicker. The rate of decline of endogenous insulin production is much faster.

Yeah, they, they might present with 90% of their beta cells gone because the autoimmune destruction from 100% of their beta cell capacity to 10% could occur in a matter of months, almost by definition, must in a kid who's six months old. But if, you know, I'm 53, if I got type 1 diabetes, I could smolder along for years. And again, I have a friend who's my age who is essentially my height and weight, and he has new onset diabetes and we think he actually has cryptic type 1. And it's slowly smoldering, it seems to be slowly progressing. It's been very difficult to precisely make the diagnosis.

And I want to come back to that in time for at least one reason, which is for people out there listening. There are people getting caught between these crosshairs that are potentially being misdiagnosed outside of the intellectual exercise of getting it right, which we love to do. As doctors, are there treatment implications that are more relevant? In other words, if you have someone who's walking around with, quote, unquote, type 2 diabetes, but they're really late onset type 1, are we also potentially caring for them incorrectly? So I'll park that because there's so much I want to go back to in type 1, but between the two of us, let's try to remember to come back to that. So I didn't actually realize the B cells played a big role, but I guess that makes sense. So I thought it was just a CD4, CD8, CD25 problem, but it's beyond that.

Yeah, there's this idea of an antigenic spread. So, again, if the beta cells make very unique things, and when you break them open and destroy them, you begin to dump them out, there is both a B and a T cell response. And we know this because we can test for antibodies in the serum of people with type 1 diabetes, and they make unique antibodies against insulin and GAD, glutamic acid decarboxylase, as well as a protein tyrosine phosphatase called ICA512. And so those antibodies are commonly used in the diagnosis of type 1 diabetes, which we believe to be a T cell disease. But again, that doesn't make any sense because antibodies are made by B cells, so there must be some contribution. And the definitive proof of that was in a New England journal article that was done by my friend, the late Mark Peskovets, and he used in a huge clinical trial rituximab, which alters B cell function, alters the ability of the B cells to make antibodies, and they were able to delay the course of type 1 diabetes.

So they were able to intervene in a subset of patients that were progressing slowly enough. They presented with positive GAD antibodies, but they still had beta cell production. You whack them with rituximab, you at least take the B cell component out of this. And if the control patient isn't having that, you now create a Kaplan Meier curve for a beta cell.

That's right. That's right. And so they were only temporarily able.

To alter how much did they delay the onset.

So rituximab is quite potent, so the circulating antibodies were reduced dramatically. They only gave a single set of infusions, and if I understand, remember this study correctly, they got a response, but it was not statistically significant at a.

Year based on one single dose.

I'm not sure we'll pull it up.

Yeah. Okay. Are there any other Autoimmune diseases that share this phenomenon that you're aware of, where you have this B cell T cell component?

Well, I think it's true of a bunch of the other autoimmune endocrine disorders, such as, for instance, autoimmune thyroid disease, where you can get thyroid peroxidase and thyroglobulin antibodies. And again, we largely think that that's a T cell mediated disease. And by the way, autoimmune thyroid disease is associated with type 1 diabetes or vice versa.

Meaning patients who will go on earlier in life to develop type 1 diabetes would be much more likely than patients without it to go on to get Graves disease or some of the other autoimmune thyroid disorders.

Yeah, typically type 1 would present first and then they can get autoimmune thyroid disease, but they can also get adrenal disease. And. And we also see, for instance, rarely sialitis, which is autoimmune disease of the salivary gland, and even rarely, autoimmune oophritis of the ovaries, as well as pernicious anemia, the ability to produce B12. And so that's presumably an autoimmune disease of the cells that make B12.

Wow. I didn't actually realize that there was so much overlap between these. Let's clarify one other thing that I'm sure someone's wondering. One thing that parents, I think are pretty mindful of is what do we have to feed our kids to minimize the risk of them getting anaphylactic reactions to nuts or things like that, given the consequences of such things. Not to get off into the weeds, but it's probably worth explaining why that's a completely different process than what we're talking about with the autoimmunity with respect to the endocrine. So not to put you on the spot, and I'm happy to fill in the gaps, but what is it about a kid, when they eat a peanut, that leads to an anaphylactic reaction? And why is that a totally different type of immune response?

Well, I should just say, in terms of anaphylactic reactions for peanuts, it turns out that you probably want to eat peanuts to avoid the anaphylactic reaction. Isn't that amazing?

That is certainly what we believe now. Right. I think the literature has become crystal clear that early exposure is better.

Right.

But again, that's a very different type of immune response, isn't it?

Right.

That's mediated by ige.

Right.

That's a hypersensitivity more than an autoimmune response, Is that correct?

Yeah.

So, borrowing from that, though, do we believe that there are any exposures that are withheld from kids that may be predisposing them to beta cell destruction, or do we think it has much more to do with these diffuse genetic issues, which I want to come back to these quote, unquote, environmental issues. And then, of course, what seems to be the majority of it seems to be stochastic.

So there's no one precise thing. And moreover, I don't believe that parents who are listening to this could say, okay, I want to make sure that my kid doesn't get type 1 diabetes, so we're not going to eat any enriched carbohydrate and then we'll mitigate that risk completely. However, that said, in populations you can see these very subtle Differences in type 1 diabetes risk depending upon the body weight of children, which implies that the standard American diet may be predisposing the population in aggregate ever so slightly towards more type 1 diabetes, which is a scary thought.

Yeah. The challenge, of course, is because the environmental contribution is so much smaller here than it is in type 2 diabetes. We don't know if we could be looking at genetic differences that could explain that. In other words, we can't do the experiment as easily. The epidemiologic comparison, I guess, to be more rigorous in my terminology, of comparing a US Population to pick a completely different population that is genetically completely distinct and environmentally distinct. We could get fooled by that, right?

Yeah. But there is a pretty nice study using the T1D exchange data, which is a large consortia of clinics around the United States. And in fact, there's a paper that was published by Maria Redondo and several other friends of mine describing explicitly these relationships in between body weight and the potential risk for Type one.

And do you remember just directionally, when a child goes, I don't even know kid body BMIs like my little guy who you just saw, who's like 97th percentile in height, weight and 95th percentile in head circumference. I was looking at his little pediatric sheet the other day because he went to the doctor and he was like, BMI of 19.4. So kid BMIs mean, I don't know how to think in those BMIs. But I was going to say, like, what's the difference between a BMI 16 and a BMI 20? Like, how much of an increase in relative risk do you see?

Pediatricians like me never able to memorize these things. You've got to put it on a You know, we have to plot it on a chart. So there's growth curves, curves for both height and weight and head circumference and weight versus height or also body mass index. It's just so complicated. And there's different curves for boys and girls.

Yeah, yeah. Okay, so question one out of the way is, is there anything I can do or a parent can do to reduce the risk of our kids getting type 1 diabetes? The answer is probably not. Other than if you want the wind a little bit at your back as opposed to a little bit in your face. If your kids can be of closer to normal BMI than not being aware.

That it is a possibility and being able to inform yourself and your neighbors and your school teacher, undiagnosed type 1 diabetes is very dangerous for children and we need to do a better job of detecting it early.

Yeah, with 1 in 300 kids getting it, that is, I mean that means in any given school one to three kids are being diagnosed a year, which is interesting because I just don't have that recollection, you know. But it may speak to this issue you've talked about, which is we just under diagnose it. We've sort of talked briefly about genes, but obviously this is not going to fall in the category of single gene mutations like the glycogen storage diseases or some of the other errors of inborn metabolism. Do we have even a quasi sense of how heavy the genetic contribution is and what those genes may actually do.

From a functional standpoint, we understand it pretty well. And though there's still a lot to be learned. So it's complicated in that there's essentially two different themes of the genetics of type 1 diabetes. One are these HLA alleles, like this is the human histocompatibility locus, and there's certain alleles that are quite common in the population that when combined place people at higher risk. And so there's something called HLA Dr.3 and Dr.4. And these alleles tend to run quite frequently in the US population. And as a result, people who have type 1 diabetes typically will have about a tenfold risk of having a child with type 1 diabetes relative to the general population.

And to be clear, is that assuming they inherit the same HLA type or independent of the inherited pattern of their hla. Because if you are HLA to doctor Your kid has a. Is that a co dominant inheritance? Is your kid 50% likely to get that? Assuming your wife doesn't have that.

Yeah. But what happens is it's so common that your wife may have that. And so just statistically, because children end up having it, the people who have type 1 diabetes often have these alleles and also these other minor alleles that contribute each very small amount, but in aggregate quite a bit. So the analogy I use is it's sort of like let's play a poker game, if you will. We're going to play a poker game where on your left hand we're going to play 21, and on the right hand we're going to play five card stud. Okay. And so when you deal me. And by the way, the winner is the one.

So when you say 21, you mean blackjack.

Blackjack, exactly. Blackjack in my left hand and five card stud on the right. And when you're dealt the cards, you have the HLA alleles, which is blackjack, because there's only a few. And they sort out however they sort out. In the right hand you're playing five card stud. And in fact, there's a huge number of combinations that could come in five card stud. But together, those two hands determine the risk. And so it's quite complicated because you can't draw a direct line in between one gene or a group of genes. But in aggregate, the statisticians think that people are approximately six to tenfold at greater risk. If you have somebody who have type one to have a direct relative.

And so if you're someone with type one, that's still not a reason to get completely panicked because that means you're. It's still unlikely your kid is going to get type 1 diabetes. Right. If you have a disease that's hitting 1 in 300 and you have a tenfold increase, it's going to hit 1 in 30. There's still a 97% chance your child is not going to have type 1 diabetes. If you do. But it would have been a 99.7% chance, hopefully, if you hadn't. If I'm doing my math right.

But there are these families. I've met them. You know, I met one family where all three sons had type 1 diabetes.

Oh, God. And was the age of onset comparable in each of these children?

It doesn't necessarily align. That's kind of an interesting and surprising element. Yeah. And actually I at one point cared for identical twins who were discordant for type 1 diabetes.

Well, that's. I was going to ask you that. What is the twin concordance? Identical versus fraternal.

So identical twin concordance within the first few years is only around 50 or 60%.

But by adulthood, what is it by.

Adulthood, it's approaching 80%. So there's a big cohort that Dr. George Eisenbach studied many years ago. So over time, those are the people. The discordant genetically identical twins are probably the people who Would they have diabetes? Not otherwise specified, but in fact, they have type one that's, that's cryptic.

And the fraternal twins, which would at least allow you to hopefully, as much as possible, normalize the environmental similarities, but somewhat reduce the genetic variability or the genetic similarity. Do you have a rough sense of what the concordance is for those by adulthood?

I don't know the exact number, but again, I think they're approximately tenfold relative to the general population.

Got it. Wow. So. So let's fast forward a little bit and get back to what we talked about over dinner in Houston a few years ago. Again, it was either three or four years ago, but it was the fall. I remember it was definitely a fall. At that point in time, I had spent very little mental energy thinking about type 1 diabetes, because obviously I'm not going to take care of somebody with type 1 diabetes. It's so far outside of my skill set. And so I sort of remembered a few things because in residency, two of my CO residents had type 1 diabetes, which is, wow, that's pretty unusual in a cohort because the categorical residents in general surgery for our year at Hopkins, There were only seven of us, right? And two of the seven had type 1 diabetes. And I, you know, I talked with them a lot about it, and I sort of remember directionally. Their target was a hemoglobin A1c of about 7.5, and they lived on crackers and orange juice, where they're sort of staple foods to manage these bouts of hypoglycemia. Certainly remember one of my buddies, it wasn't uncommon if in the middle of an operation, one of the OR nurses would have to come and put a little straw behind his mask and he would have to drink some orange juice to sort of, you know, manage his glucose levels. And then when you and I sat down for dinner, you said, you know, your average patient is walking around at something like 5.7, 5.8, 5.9 hemoglobin, A1C. And that immediately caught me off guard because I was like, oh, that seems very different from what I sort of remember. So how did you get from wherever? Presumably you finished your training and entered your practice. I'm guessing that was sometime in the late 80s, early 90s.

I graduated from fellowship in 2000.

Oh, okay. So over the last, call it 15, 18 years, how did you evolve your thinking around targets for where the hemoglobin A1C? And I guess I should take a step back and also explain for someone what the hemoglobin A1C is, since I'm so critical of it in general. By the way, you've probably heard me rail on the futility of it. The hemoglobin A1C of course, measures the amount of glycosylation or how much glucose is sticking to hemoglobin. And if we take the assumption that hemoglobin has a relatively finite, fixed, predictable life before the red blood cells themselves get broken down, we can measure the hemoglobin A1C and then impute the average blood glucose. And that's of course, the exact opposite of what we would do with cgm, where you are actually measuring the average blood glucose and imputing what the hemoglobin A1C would be. So the diagnosis of type 2 diabetes is made today solely on the hemoglobin A1C being greater than 6.5%. It no longer relies on the insulin or glucose level during an oral glucose challenge. Remind me, a hemoglobin A1C of 7.5 corresponds to an average blood glucose of approximately, what, 160?

Yeah, I think that's right.

We'll post the table to it. It could be 150, but it's directionally in that ballpark. Right, right. So for someone listening to this thinking, God, that seems a little high. Why was that chosen as such a goal?

Okay, so we should first just talk about the dcct, which is the so called Diabetes Control Complication Trial, which after the discovery of insulin by Banting and best in 1922.

In Toronto.

Right, In Toronto, that's right. So we're coming up on the 100th anniversary of the DCCT, the discovery of insulin.

Can we detour for two seconds and explain how Banting and Best did this? Because it's really one of those beautiful stories in medicine.

Yeah, it's so amazing. And there's a book, by the way, which is by Michael Bliss, called the Discovery of Insulin. And if anybody has a vague interest in type 1 diabetes, they should run and buy this because it's just so amazing and bring tears to your eyes.

Prior to Banting and Best, what happened to children with type 1 diabetes?

Children or, or adults. Yeah, or adults. So at least in the 19th century, nothing. So these people would present with weight loss and history of drinking and, and urinating quite a bit. And over time they had to manage their expectations and then they would expire.

And it was, I assume usually from complications of diabetic keto astro.

Yeah. And so it would happen in a matter of weeks, some cases days, in some cases months. Then along came Allen and Allen created this amazing so called Allen diet. And that was essentially a low calorie, high fat nutritional regimen that had almost no enriched carbohydrates. And if you use that approach, they were able to extend life to a few months, in some cases a few years. But it required incredible precision. And Dr. Joslin and others had adopted this approach in a desperate attempt to extend life. But other than that, there was nothing you could do and people just wasted away. So it was one of these things that people feared greatly because if your kid got type 1 diabetes, that was it, you were going to watch them disappear.

And you said this earlier, and I didn't interject, but it's probably worth reiterating. You talked about how important insulin is. You use the term catabolic, but in contrast to its role, which is as such an anabolic gatekeeper, and therefore in the absence of it, you enter this catabolic state. So talk to me about what you mean by the anabolism of insulin.

Ultimately, insulin is a key factor that's regulating virtually every cell in the body. And it's essentially deciding whether a cell is in a state of feast or famine. And so if you're in feast, it's time to take nutrients and park them in the cell. And if it's famine, hey, let's mobilize some nutrients and make them available to keep the organism alive. And so it's a master regulator of your state of metabolism. And so if you take a normal, non diabetic human and you fast them for 24 hours, you discover that their circulating insulin values, especially of a healthy young adult, are exquisitely low. But if you then take that same person, you give them a 75 gram glucola challenge, you can get their insulin values to exquisitely high levels. So it's a dynamic hormone. It's changing rapidly in response to meals and everything else, and it's helping you to sort of take these nutrients and park them away.

Now, in the fat cell, I think most people have a vague notion of what's going on. There's basically one door into a fat cell of esterification or re esterification, and then there's the door out, which is lipolysis. And insulin acts very prominently at both of those. So free fatty acids and triglycerides are highly regulated by insulin at both ends of that adipose cell. What is insulin doing at a muscle cell?

It's promoting glucose uptake into skeletal muscle. And it's a dynamic process that involves GLUT4, these glucose transporters. And essentially the glucose transporters are normally sitting in the cytosol, and they translocate to the cell wall. And now all of a sudden, the muscle cell becomes permeable to glucose, and glucose is pumped in.

So glut 4 is a passive transporter. As long as it's going across the cell membrane, glucose enters freely. The active part of that is the insulin signal that tells the glut transported to go from the cytosol across the membrane.

Right.

And then so taking the other extreme of that, which is when someone is fasting or starving, which is effectively what's happening in type 1 diabetes at the cellular level, they don't have insulin. How does the lack of insulin promote the breakdown of actual muscle? So this negative nitrogen balance, Because I'm assuming that while a lot of that muscle that breaks down is used for gluconeogenesis, wouldn't that patient, if you're measuring urinary nitrogen levels, also be in a profound negative nitrogen balance?

Yeah, every step of protein metabolism, many of the major steps are influenced by insulin as well. So you're either making proteins or you're breaking them down. It also influences the glycogen that's in skeletal muscle and heart and kidney. So in the presence of insulin, you're putting more glycogen into skeletal muscle, or in the absence, you're going to break it down or also with just work.

Boy, it's a thin razor's edge, that hormone. Too much of it, really bad stuff, too little of it, really bad stuff. As long as you can control it, it's a pretty wonderful hormone.

And because it's so fundamental to eukaryotic cells, it seems to also influence things you would never even IM like, for instance, lifespan and aging. And so it's really a deep and fundamental signal around where cells are.

Do you have a great sense of how insulin relates to igf? It certainly plays a role in the inverse relationship between some of the binding proteins. So we know that as insulin level goes up, sex hormone binding globule goes down, and therefore high levels of insulin will all things equal reduce the level of circulating androgens because more of them are being bound up. What's the relationship between insulin and the binding protein for IGF? IGF binding proteins 2, 3, et cetera.

I'll probably get this wrong, but I think it's IGF one can go down in the presence of high levels of circulating insulin acutely. And it's one way to be able to diagnose a very short term hyperinsulinemia. This is something that we often struggle with in pediatrics. We bizarrely even have some people who will take way too much insulin trying to pretend that they have hypoglycemia by some measure. And then we go and measure in the blood and you can actually measure for IGF BP1 and it can be down.

So the BP1 goes down. So in many ways IGF would go up. Then if the binding protein goes down, the free IGF should be going up with insulin. Right.

Assuming I remember this correctly.

Well, that's sort of what I see clinically. Right. The more hyperinsulinemic a patient is, all things equal, the higher you tend to see their igf. And that's always been my assumption as to why, just based on the parallel analogy with these, I'm ashamed to say I'm too lazy to have spent the time looking this up.

Well, the other thing I would just point out is that insulin and IGF1 really are intensely overlapping in the way they work. And insulin does not bind as a monomeric hormone. It's actually a dimer and it can be a heterodimer. So you can have two insulins, or you can have an insulin in IGF1, or you can have two IGF1s and they can bind to receptors. And there are even hetero receptors where it's an insulin receptor and an IGF1 receptor, each bound by their cognate ligands. Derek Leroith at Mount Sinai has done this kind of work for years. And when you block these heterodimeric receptors, you can completely alter metabolism, implying that the role of IGF1 on glucose homeostasis is really quite powerful.

Yeah. And we probably won't get to it today, but there's also igf and its relationship to growth hormone is actually quite interesting when it comes to diseases because it seems to have very different effects on different diseases. There are certain diseases that seem to go up in risk as IGF goes up, and there are others that seem to go down, whereas insulin seems a little less confusing. But we'll obviously come to that. So in the late 1910s, when Banting and Bester, working with dogs, do they know that they're trying to isolate? Like, do they have a sense of where to look for this hormone?

Yeah, so Banting has an idea. Actually, the story of how he comes up with the idea is amazing and really surprising. So he's a surgeon in a dead end practice in London, and this is London, Ontario. London, Ontario. And he can't make his mortgage. He's a. He's a veteran of the World War. At that time there had only been one. And he's trying to get this general surgery practice going, but he's bored and he doesn't have that many patients. And so he's a reader and he's thinking about ways to try to contribute. And he reads in this journal article which describes how people who have stones in the pancreas end up with these strange islet like structures or islands of cells. And so essentially what happens is the pancreas, for whatever reason, if it's obstructed by a stone and it has a blockage, what you end up with in the residual after the pancreatitis occurs are these weird round cellular structures. And so it had been known from a couple other scientists that there might be something in there that was involved in diabetes. So he comes up with the idea of, wow, maybe what I could do is block the outflow of the exocrine pancreas, which makes these digestive enzymes force the pancreas to eat itself alive. And then I will take this residual muck that comes from the pancreas and try to purify whatever is within it to see if that is some sort of medicine that might be useful for type 1 diabetes. It's a genius moment that comes to him in the middle of the night. He writes it down. Michael Bliss actually found the notebook page from his bed stand where he wrote this. And so then he goes to the University of Toronto, which is this very sophisticated place, and he meets and he knocks on doors and he finds this guy who's a famous professor of metabolism. And he says, I got this incredible idea. I want to isolate this thing that must be in the pancreas. That would be the treatment for type 1 diabetes. And the guy's like, you're out of your mind. He's like, no, no, no, it's a really cool idea. Let me tell you about it. And what happened is this professor is about to go on break for the summer and, and to go off to Scotland. And so he leaves Banting with a very short lease. He says, look, I'll allow you to do a few experiments and I can give you a few resources, but you basically got to finish your experiments by the end of the summer. And so Banting is there, and then he essentially gets a medical student who has the dumb luck to draw this crazy experiment with Banting. And that's Charles Best. So there they are in this cramped, hot laboratory in Toronto and amazingly, they are able to isolate this substance that has the ability to lower blood glucose in dogs.

And they're doing this in dogs as well.

Yes, that's right. So they do these. So what they do is they carry out this intervention, the pancreas eats itself alive, they get this muck and they are able to isolate some crude extract and then take it to and put it back into a dog that they've removed the entire pancreas of and lower the blood glucose. It's like this incredible moment. I mean, and this is 1922. What's even more extraordinary is that they're able to take this observation and then they eventually, fairly quickly, do an experiment where they lower the blood glucose of a medical student who has type 1 diabetes with this super crude extract. So they're able to prove that it works in man. And so then they write the paper and the paper gets rejected and then they're able to submit it to a Canadian journal and it gets accepted.

That low Canadian bar, I love it, man. That's been the secret to any success I've had.

And they ultimately won the Nobel Prize. It's amazing. And if you think about 1922, and.

By the way, it's sort of one of like every year there is a Nobel Prize awarded in medicine or physiology, I believe is the designation. And there are a handful of them that stand out in a way that can't be described. And this is one of them. The Banting and Best Nobel Prize is one of a handful of places where the trajectory of clinical practice was altered dramatically.

I think just by virtue of the fact that we're both physicians, we can feel proud by association that our profession was able to do something so remarkable.

How long was it before recombinant insulin was used? Because after Banting and Best, they were still using insulin from animals.

Yeah, purified from pigs. It's amazing. It went on for years and years. And they would take these giant vats and it was either from beef or from pigs.

It wasn't until the 80s, if I recall, that they figured out how to make insulin inside of E. Coli once.

Paul Berg, Genentech yeah, so there's an amazing article about the molecular biology of modern insulin. And you know, that was basically a race and it was a bunch of.

It really was. It's A biotech arms race to figure out like. And it's. Some of the greatest stories in science are of that arms race of the 80s.

They knew that human insulin could be incredibly useful for this population. And part of the reason is if you're taking a foreign product like pig insulin, you can develop antibodies and in some cases those antibodies can be blocking to the point where insulin you start to have to increase the doses greater and greater. So human insulin was known to be a goal and they were eventually able to produce it. Genentech did this, they sold the rights, and now there are multiple modern human insulins on the market.

Not to get into a controversial topic, but can somebody explain to me, and you can opt out of this question if it's too politically sensitive, but can somebody explain to me why the hell recombinant insulin is still so expensive?

Well, what's interesting about recombinant insulin is it used to be cheap. So back when I was a fellow, a vial of insulin, which is 1,000 units, cost about 25 bucks and that would last.

That could last a well managed patient for a month.

A month or more. Right.

And today, what is a thousand units of recombinant insulin?

300 plus maybe $400 US right now.

I don't know a lot about economics and I kind of forgot my tables of inflation, but I think I feel like that has outpaced inflation a little bit. So how is it that we have more competitors in the space, better technology today, and we've watched a log fold increase in the price of this stuff that must be driving a lot of people nuts, including those who can't, who don't have insurance, and frankly the insurance companies themselves that have to pay this.

It'S a disaster on many levels. It's really a disaster for people who are on the margins of society but want modern care and are willing to pay for it, but they can't get insulin at the same price that for instance, you could, if you walked into a pharmacy in Spain, you could buy a vial of insulin for 25 bucks there, it's 3 or $400 here. The difference, unfortunately, is that the federal government is, how shall I say it, a promiscuous customer. So they thus far have not been able to drive the price down because they're willing to essentially pay whatever the sellers charge. And that's a big problem. And it speaks to the lack of market influence in things like insulin.

So now let's go back to where I distracted you from a long time ago, which is you finish Your fellowship. You're a card carrying pediatric endocrinologist who knows how to target highish levels. And we were about to talk about the trial.

Oh, yeah.

The details that explained the complications that basically led to the why we care about this.

Okay, so if the discovery of insulin is like the first real modern chapter in type 1 diabetes, then the diabetes control complication trial is chapter 2. And it's based on a brilliant and very clear idea which goes, if people with type 1 diabetes are at risk for terrible complications, and we haven't really said this, but they're at risk for all the complications that people with type 2 diabetes get. Cardiovascular disease and kidney disease and diabetic retinopathy and blindness and limb amputations.

Well, actually, I'm glad you brought that up because I've been a little delinquent in my job as host and taking things for granted. Can you explain why people with type 1 or type 2 diabetes have so many of these complications that we refer to, I guess loosely as microvascular complications? And. And we'll get to the macrovascular, of course, but just start with those ones you mentioned. Why the amputations? Why the blindness?

The blindness is from abnormal vessel growth. And it appears that there are these weird glycations that can occur and there's a series of damages that happen in the vascular endothelium. And then there's new vessels that are created and the new vessels are fragile and they can ultimately break and bleed. And the kidney, it's a very different set of mechanisms, but basically very high glucose can alter the epithelia of the kidney that's involved in filtering blood and making urine.

And then why the amputations of toes and things like that?

Yeah, so that's altered healing from a couple of things. So one is that there's something called diabetic neuropathy, where the nerves simply don't work well and exposed to high glucose, they lose their responsiveness. And so sometimes people will, for instance, have a wound in their foot, but they're not able to actually realize that they have that wound. And so then they also have abnormal healing because the microvasculature isn't behaving appropriately. And the sum total can be very bad diabetic wounds that fail to get better with antibiotics and ultimately result in amputation. And this is like the most common cause of preventable amputation in the United States. It's also the most common cause of preventable blindness in the United States and probably also renal failure.

Yeah, I was just about to say it's gotta be the leading cause of kidney disease. So the relationship between the average blood glucose, which we proxy by this hemoglobin A1C, and these complications you mentioned, that's a monotonically increasing relationship, correct?

Pretty much, yes. So the DCCT really figured this out. So at the time they designed this trial, they're thinking, well, all this terrible stuff is happening to these people with type 1 diabetes. And so there was a group of people who thought, well, it's just genetics. You know, it's obvious because we have two patients and one who has pretty good control, the other one has pretty good control, but one gets complications.

What were the years of enrollment in the DCC?

So this is in the late 80s, actually, mid-80s. And it was reported out in the New England Journal, I believe, in 1993.

And prior to that, you're saying it wasn't obvious that the differences in these complications could be explained by the differences in their average blood glucose?

That's right. And there were endocrinologists who believed quite strongly that it was foolish and perhaps even dangerous to carry out a clinical trial to test the basic idea. So the core idea is, does tight control that is near normal blood glucoses confer protection from diabetes complications? And the primary outcome measure was, were microvascular. It was kidney and eye.

And the reason that these physicians, who we can look back at now and obviously with the benefit of so much hindsight, sort of consider that their views were silly, they weren't bad doctors. Right. They had something to be afraid of on the other end of this.

Right. They were concerned about hypoglycemia.

So talk about that for a moment. That's it. Because there's got to be a really bad boogeyman on the other side of this for people to be so worked up about letting glucoses get really high.

So the issue with type 1 diabetes is we think that hypogluculoses are conferring risk of complications. But the problem is you can't just throw in a bunch of insulin and then normalize glucose because you will cause somebody to go low. And with type 1 diabetes, the crux of the problem is the volatility in blood glucose. So it's not just so simple that you can figure out the amount of carbohydrates you're going to eat and take some insulin, and your blood sugar is.

Going to be normal, because even if you eat the exact same thing every single day, as anyone knows, who has type 1 diabetes, and I only know this because of friends who have it, your level of stress, how much sleep you had last night, how much exercise you've done or not done, can even in the presence of the identical foodstuff, produce completely different insulin requirements.

And the other things in food, like fat and protein, also alter gastric emptying. And the end result is a tremendous amount of slop and variance in the system. And so we in the medical field often have this fantasy that, well, we can just come up with some sort of formula for here's your insulin to carb ratio. And so I tell you that, and then you're supposed to follow it. And then if you come back and your blood glucoses aren't exactly perfect, I, the physician would say, well, you obviously didn't follow it. You're, you know, they use this terrible term in medicine, non compliant, which means you didn't comply with what I told you to do. It's grotesque.

In no format or no arena is it more ridiculous than this one when you realize how difficult this is. And as I learned from a patient of mine, actually, this was actually probably the first person I was ever involved in the care of as a medical student. And we became very good friends. He ultimately died from colon cancer, but he was a pilot. And after, during one of his bouts of, you know, sort of remission, he took me flying and he actually let me fly. Once we got up, he, you know, he took his hands off the stick. I had a stick and I was flying. And he said, you got to look at the horizon, don't look at the instruments, because if you look at the instruments you're going to constantly be chasing them and you're getting to this pilot induced oscillation. And obviously that's called instrument flying, which you learn to do way down the line. But as a total rookie, you have to be able to fly off the horizon. And it was amazing to me how much easier it was to fly that way. And in some ways that's what happens when patients or physicians would get frustrated with this inability to manage this is you tend to go too high, then too low, then too high, then too low, and then you are vacillating wildly in these glucose levels.

And again, yeah, you see these huge sine wave excursions and some of them can be incredibly volatile. So I'm going to go back to the dcct. So they have this idea that they're going to somehow normalize blood glucose. But then there are some people, physicians who say, well, that's a terrible idea because you can't actually normalize blood glucose because you're going to make a bunch of people hypoglycemic. So there's a group of people who are arguing against the dcct, there's another people, including Elliot Joslin, who are saying no, we need to understand if we can reduce the risk of long term complications. So they carry out this trial. It's intended to be a 10 year clinical trial and it's 1441 patients. They're relatively recent onset type 1 diabetes. They're largely late teen and adults. And it's a very difficult trial to do because there were no established best practices to achieve neuronormal blood glucoses at the time. So the average hemoglobin A1C for the population is around 9%. At the time, that was just where they were.

That's the lowest glucose you could have to not have hypoglycemic events, right?

Yeah. And sort of that's where people were in order to not dump massive amounts of glucose in their urine and sort of look, okay. And in some cases people were taking insulin once a day. Quite often people were taking insulin once a day.

And someone who's got a hemoglobin A1C of 9% is not going to live a normal life. Their life expectancy is truncated dramatically and their quality of life is going to be even by their 40s, they're going to be quite compromised.

Yeah. So we know now from Swedish studies that somebody with abirate hemoglobin A1C has about a what of 9 of 9% has approximately a six fold increased risk of death and a six fold risk, increased risk of cardiovascular disease. And so that's shocking. And again, these are healthy people who are doing their best, but the system just didn't work. So in the DCCT they say we want to normalize blood glucoses in the population and try to get them from, from nine all the way down to the non diabetic range, somewhere under six. And they put together all of these centers and what they did was they mandated conference calls and on the conference calls they shared best practices, they crowdsourced it, if you will. And so they didn't have any idea how they were gonna achieve their goals, but they ended up ultimately learning how to do it. And it involved phone calls and it involved frequent visits and cajoling. And they're able to reduce A1C from 9 to 7% in the population. They intend to do this for a decade. There's a safety and monitoring board that's following the curves. The primary outcome measure is Diabetic retinopathy and diabetic nephropathy. And the safety and monitoring board sees a huge difference in between the control and the intervention group. And they stop the trial. And the reason is they felt that this was seven years in, and they felt that they.

It was now unethical in the reverse.

Yes, it was unethical to deprive the general population of what they had learned. So. So they stopped the trial. There's a giant talk at the American Diabetes association that describes these immense differences. There's a paper that's in the New England Journal of Medicine. It's amazing, wonderful paper. And it changes type 1 diabetes forever because it says that we can begin to reduce complications. And the work that we do is incredibly important for this patient population. In some ways, it makes the field of modern type 1 diabetes care because it says there really is something you can do other than hold somebody's hand and look for complications. But on the other hand, it actually breaks the field because we don't have the apparatus to routinely achieve the kinds of outcomes that the NIH was able to do. Because they had near infinite resources. They spent over $100 million for a relatively small number of patients.

$100 million for 1400 patients over seven years.

Yeah.

That's a staggering sum of money. Where did it go? I mean, and I'm not being critical of that. I'm just saying, like, what was so expensive about that study?

Coordinating centers and, you know, buying people's time to be able to care for them, to call them, cajole them? There's a lot of. There's a lot of work that was done. Wow.

I did not realize it was that expensive. And that's 30 years ago's dollars.

Yeah, I could have it wrong. We'll have to look this up. Okay, yeah, we.

We've got the team to look that up. But. But I'm guessing directionally you're right, that it was. It was a cost amount of money.

Yeah.

Was there a sizable or noticeable increase in the hypoglycemic events with that tighter control from nine to seven?

Yes, there are many more hypoglycemic events. And there was weight gain. And so when they jack up the insulin, people found themselves eating more carbs and eating out of the hole. And over time, was that actually the.

Case that they know that the people who gained more weight consumed more of one type of food than another?

No, not necessarily. But practically, if your blood glucose is low, the only thing that's going to get your glucose back up is carbohydrates.

Oh, so I see. So it's. They were chasing carbs when they were overshooting on insulin.

Right. And this is one of the continual problems with type 1 diabetes is if you jack up the insulin and your blood glucose is low, there's only, only one thing you can do to get your glucose back up. I guess you could go out and you could exercise intensely, but it won't happen fast enough. So acute carbohydrate is essential.

So we don't really know. Not to get off on a tangent, we don't know if those patients gained weight because of the hyperinsulinemia per se, as a primary driver, or if it was sort of not necessarily a root cause, but more of a tangential driver that ultimately forced more of this sort of hyperphagic response indirectly to compensate.

You're asking a really important question, which is, is the weight gain in type 1 diabetes absolutely obligate? Is it coincident with type control? And it was argued by many that the only way towards tight control would be weight gain. And by the way, in the years since the dcct, what we've seen is a huge number of people with type 1 diabetes have gained weight, in some cases uncontrollably, and that is a really serious problem. And moreover, in the people who have gained the most weight have had poor cardiovascular outcomes, there's a weak association. So I want to just talk about the bigger picture of the DCCT so that the trial only happened for seven years, and then the cohorts merge back to the same blood glucose, and now they're followed for 25, 30 years.

Wait a second. When they merged, did they merge to 7 or merge to 9?

Yeah, they merged to 8. So what happened was the people who had hemoglobin A1Cs of 9 learned the benefits of tighter control and they did their best.

And the people at 7, no longer under the, you know, grip of the best in class care, drifted up to eight.

That's right.

It became where people landed.

Eight became the new normal with a significant standard deviation within it. Some people just did better or worse. And then you follow these people over the subsequent 23 plus years, and it turns out that there are immense differences in major kidney disease and in cardiovascular disease and even death.

So the people who, at least for 7 years had tighter control versus less tight control, but then for 23 years were identical to their peers, still retained some benefit from the seven years 30.

Years earlier in cardiovascular disease, which is amazing, and death.

So that what kind of hazard Ratios, do you recall?

I'm not sure I'll be able to remember it off the top of my head.

We'll link to all of this stuff.

Of course, at least in the primary outcome measure for the, for the cardiovascular trial, it's approximately a third less of the primary outcome measure. So that's really exciting. And it suggests that if you were able to routinely achieve blood glucoses in the near normal range, you could drop your risk cardiovascular disease accordingly to something that was approaching a normal, healthy, non diabetic person. That's pretty amazing. But it also puts a lot of pressure on us as a field.

So if you were to have a device, a magical device that could measure someone's glucose in real time, and you were to put this on somebody 30 years ago, back when the standard of care was, you know, minimize the hypoglycemic events, we're going to tolerate a hemoglobin A1C of 9%. Can you estimate what the standard deviation of glucose would have been on that measurement? Do you have a sense of how high that could have been?

Yeah, because I put continuous glucose monitors on teenagers who don't listen to me.

Okay, so talk to me about some of those numbers.

Yeah, so you might see blood glucoses of around, in some cases, 180 or 200 with a standard deviation of 100. And so again, poorly controlled type.

You know, my standard for myself, right. Which is under 20, 90 plus or minus, if I'm fasting or on a, you know, sort of ketogenic diet, I'd like to see it plus or minus less than 10. And when I'm just eating ad libitum, it's sort of less than 15. Yeah, 100 is amazing.

100 means you're bouncing around nonstop, which again, never normal.

And you feel so bad for these patients because even if they intermittently decide, okay, today's the day, I want to get this right, like you just can't chase that down. That is so difficult. I don't even know. It's hard for me to physiologically even think about what's happening in those patients.

And so that kind of volatility has just driven everybody insane because they think, like, there's gotta be a better way, there's gotta be a better way. And, you know, anybody who lives with type 1 diabetes, they're constantly being asked, okay, well, what about a cure? I. I hesitate to even use that word, but, like some sort of definitive biological therapy. And, you know, and we've heard all along about the possibility of stem cells or or some sort of maybe an auto loop pancreas that would measure your glucose and administer insulin, or maybe some sort of beta cell regenerative therapy or something combined with something that shuts down the autoimmune system. So those three concepts are constantly trotted out as potential avenues. But from what I can tell as a scientist, many of those things are years and years and years away. Decades, maybe even centuries. And so the problem is, like, what do you do now to support people who live with type 1 diabetes? How do you reduce that volatility?

So I remember reading a paper a few years ago, it was actually right after you and I met, that I got more curious about this. And especially then once I started wearing a cgm, which was shortly after that, and I've basically never taken it off, I started to figure. I started to think, okay, well, from my angle, it's how do you use these in people who don't have diabetes to drive better health?

Right, right.

And one of the questions I wanted to understand was, was there any evidence that variability in blood glucose per se, beyond the average? So if you have someone whose average blood glucose is 100 plus or minus 10 or 15 versus someone who's 100 plus or minus 30, is there a difference? Well, the hemoglobin A1C would give you the same answer than even the average glucose does. And I believe I found some data that suggested that cognition was impaired during developmental years by higher variability.

Yes.

And I think it was even independent of absolute glucose level. And that was very frightening to me, not individually, because I was out of that loop, but thinking about kids with type 1 diabetes who now have yet another complication to be concerned with, which is cognitive impairment if the variability of glucose is too great.

It's well known that, you know, diabetes complications are increased with increasing A1Cs. A kind of surprising piece of this is very short exposures to high blood sugars can completely change gene expression in a whole bunch of genes like endothelial cells. So there's a school of thought that says that diabetes complications are really around the exposures to these weird, toxic levels of blood glucose that can occur.

And what do you think toxic is how high?

Well, they always do it experimentally by turning everything up to 11, so you never really know. But what you can say is it is surprising and weird that a short, almost evanescent exposure to a very high blood glucose could change the way genes behave and cells in a dish. And so that that suggests to me that diabetes complications may not be so simple as a Sort of on, off, in between glucose and hemoglobin or glucose and some other protein. You could have permanent, profound changes in the way a cell behaves based on intermittent exposures to very high blood glucose. So whether that's volatility or it's an absolute peak.

Wow.

But it still puts.

That's just like nature to fuck with us like that. I mean, to have to deal with some epigenetic change in response to a glucose. But, I mean, that's so unfair.

But in the end, it shows you that we had a very superficial understanding of diabetes complications years ago. And again, now there's a whole rich field that's devoted to this idea of these windows of hyperglycemia permanently altering these important cells that ultimately contribute to diabetes complications.

You're making me question my elaborate cheat meals sometimes just admit this now to you and everybody else. A couple of days ago, I was like, you know, I've been so good for so long. I've been doing my this, that, and everything. And, like, there are just a handful of junk foods I can't get enough of, and one of them is Mini Wheats. So I decided to have a box of Mini Wheats. That's not a typo. It's not a bowl of Mini Wheats. A box of Mini Wheats, meaning if you have a big enough bowl, you can put the box in the bowl. So I had a box of Mini Wheats in a bowl, and, boy, if you really want to know why that's not a good idea, just wear a cgm. And not to mention the splitting headache I had, like, an hour later.

Yeah, I get headaches.

I mean, I thought I was gonna die. I'd feel better if I had six drinks. I think my head would have hurt less. My blood glucose hit, like, 170. Now, again, that's, in the grand scheme of things, probably not that high for someone who's got type 2 diabetes or type 1 diabetes. But for someone who's not diabetic, that's a pretty staggeringly high. I haven't seen a level that high in years. And you think, like, hey, these mini Wheats are promoted as, like, healthy part of a healthy breakfast. And so imagine now no one's eating a box, but.

Yeah, but, you know, if you think about this in the context of your kids, imagine dropping your kid off. Who. If your kid has type 1 diabetes, you drop them off at a birthday party, and there's cake, and there's, you know, Capri Sun. Capri Sun. And there's Cheetos. And all this stuff is essentially carbohydrate. And if your child is.

And none of them are real carbohydrates, that's the problem, right? It's all like these fake carbohydrates. It's one thing if they were like, all right, we're gonna grind up some wheat and you're gonna have a piece of bread which has its own issues. But yeah, these things that you've described are, they're basically IV infusions of glucose.

Let's imagine you drop your five year old off at a birthday party and you know they have diabetes and you give them and they're wearing an insulin pump and everyone knows what they're supposed to do. And out of sight of all the adults, the kid eats two cupcakes. That's the equivalent of the box of Wheat Thins. Is that what you.

No, but it's funny you bring up Wheat Thins. That's one of my kids favorite things is he calls them weathens. But no, it's Mini Wheats.

Mini Wheats.

Mini Wheats, yes. It's just nonsense. It's basically breakfast, dessert.

So again, this thing was really perplexing for me. And part of when I really understood how challenging it all was was spending time with people who live with type 1 diabetes and looking and seeing what they do. And I didn't really get this as an endocrine fellow. And we had this standards feel about, okay, you're going to check your blood sugar before each meal and at bedtime, and then you're going to eat certain number of meals that involve certain number of carbohydrates. And we had this fantasy that we're just going to sort of make people live in what I call the diabetes icu, which is a prescribed number of carbohydrates and timing. And then we're going to sort of work towards making sure that everything was very predictable and then blood glucoses would be near normal much of the time. And I lived in that fantasy world, unperturbed by reality, until I became close friends with several people who have type one. And then I began to see what they do. So, for instance, my friend Marianne is a pediatric endocrinologist who works at Boston Children's. And one time we were at this restaurant and she's. We're at Bertucci's, you know, so pizza place. And she.

And, and she has type 1.

She has type 1 diabetes and she's eating a Caesar salad and I see her picking the croutons out. I'm like, what are you doing? And she goes, oh, Jake, I can't eat these things. I'm like, what are you talking about? She's like, if I eat those, these carbs, my blood sugar will just go loopy. So what I discovered.

And let's pause for a moment. You know all of the molecular biology, you know how many grams of carbs are in that, Right. You've been managing patients through their food with insulin, and now you're watching one of your peers pull out what's probably 15 to 20 grams of croutons. Like, it's virtually like it's something that wouldn't even alter your blood glucose. And yet she's saying to you, if I eat these things now, I'm really going to be chasing this for a while.

And she said, and I won't be able to figure out the right dose of insulin because of all the fat that's in the salad dressing. She goes, I've just found that it's easier for me to not eat this stuff. So I looked at that and I realized, like, this is the ultimate hack. This is somebody who figured out, like, the ultimate biohack. She's trying to make her blood sugars near normal all the time. She discovered a group of foods that she needs to avoid, and so she avoids them.

And what did she figure out? I mean, presumably most of what she needed to avoid was carbohydrates. But were there some that she found? Found, and I assume she did not have a CGM at this point in time.

That's right.

So this is all on finger sticks, and this is doing it the really hard way.

She's testing 10 times a day or something.

Yeah. God, what did her. Yeah. Do they even have feeling left in their fingers at this point?

Quite often they won't. So they go after people use finger stick testing, will use one spot over and over again, and it becomes numb. And that's a way to be able to do it without pain.

And I just know from when I'm doing a lot of finger sticking, like the bruising and the discoloration and the discomfort and. And I think to myself, you know, it's one thing when I'm doing this as a grownup who's choosing to do this, it's quite another thing for a kid who never signed up for this to be going through this amount of pain.

Yeah. And for their parents, and for the parents to think about all the other things that could happen. Like, for instance, we, you know, unfortunately we have kids who disappear, so we have Teenagers who go off to college, you know, and they party with their friends and potentially take the same dose of insulin that they would have taken and they have fatal hypoglycemic episodes. And that doesn't happen often, but when it does, it's devastating, it's really awful. And that sits in the back of parents minds. And that kind of anxiety means that nobody ever really just gets to be a parent or a kid because there's this constant fear of what's my blood sugar, is it high or low? And I think of it as a cognitive load. It's the burden of having to think nonstop about your diabetes. And if you can imagine that volatility, the roller coaster, blood sugars that are going up and down, you're going to have to think about it non stop. And I think that the cognitive load in some ways is probably a really pivotal factor in the anxiety and depression that's associated with type 1 diabetes. So there's a whole category of very complicated mental illness that people with type 1 diabetes have. Approximately 45 or 50% will have depression or anxiety. And it can be really debilitating and.

Of course we don't really have any way of knowing is what percentage or what amount or proportion of that debilitating mental illness is resulting from the physiology of the hyperglycemia, the glucose fluctuations and the hyperinsulinemia or the relative hyperinsulinemia versus this much more difficult to track metric of the cortisol levels that accompany the stress or other things that we couldn't even measure if we wanted to that accompany that, as you put it. I like that phrase, cognitive load. I mean, what's the current thinking on that? I didn't realize that the. Did you say 40% depression?

Yeah.

That seems almost impossible to believe.

Well imagine, let's imagine you have type 1 diabetes and you've lived with it for 20 or 25 years and right now you're a little bit hungry and you're trying to figure out what your blood sugar is going to be and you look down at your CGM and you get a number and you're thinking, well like what do I have to do and when do I have to time the dose of insulin and will I get it right? And think about the last time I gave insulin and I didn't give it right and I had that hypoglycemic episode and you know, it was embarrassing. And so I mean it's a big, really serious challenge and that I try to quantify what I call the cognitive load using A diabetes distress scale. And it's an adaptation of a published distress scale. And I basically say to people, okay, I want to talk to you using a likert scale, a 1 to 10 scale, about your diabetes related distress. And so it's on a one to ten scale. And one means you know you have diabetes, but it's not holding you back at all. It's there, it's in the back of your mind, it's not bothering you, you get to do what you want to do. And a 10 means you have diabetes and you can't think about anything else. And it's pretty much omnipresent and it alters your ability to carry out the things you want to do. So if this is on a 1.

To 10 scale, so what's the median score for a teenager who has had this disease for five years or more.

Who'S on a high carb diet? Yeah, seven or eight. And I've seen people who have hemoglobin A1Cs that are approaching 14, who are doing basically nothing to get to care for their diabetes. Teenagers who are really struggling. And when I describe this to them, their answer is tears pour out of their eyes. And because no one has ever actually asked them how do they feel? And they will say attend, but they can't even admit it because no one has ever considered that they have this terrible burden. What they think is, you know, this kid doesn't do what everybody wants him to do. You know, he's got a hard head, he's not listening to us. But in fact, the kid who's not doing anything is thinking about it non stop and is racked with guilt and shame. And this is not just true of teenagers, it's true of adults, because the adults want to do a better job, but they lack the tools and the support to be able to carry it out. And they blame themselves. So this endless cycle of blame and shame and negativity activity is unfortunately in many cases reinforced by the medical establishment. Because now you come in, you got a hemol of an A1C of 14, and what do you get?

He gets spanked.

Yeah, you get, you get a lecture about how you need to do a better job. You're told you're not compliant, you might even be threatened with being fired by your doctor unless you do a better job. You know, you might not be able to, you know, make appointments here. This is a privilege to come and see the endocrinologist. And so people end up in this weird cycle of antagonism towards the medical establishment who apparently don't know that much about type 1 diabetes and certainly aren't empathetic about it. And then their loved ones who are like, well, why can't he or she do a better job failing to understand how really complicated it is. And there's no well worn path in the general populace on how to get to a better spot. And so one of the really crucial elements of this, which is so bizarre, is that this diabetes distress or this anxiety or whatever it is, is ego syntonic. And so it doesn't feel foreign. People are depressed or anxious and they just think that this is the way life is going to be forever. They can't imagine another world where they would feel better. They just think that life sucks. And when you get them. I've worked with people, I've actually had the privilege of working with a few people who have dropped their hemoglobin A1Cs in half. And the experience changed my life. You can get somebody from an A1C of greater than 14 down to under 7. And when they talk about it, they're astounded by the changes in their ability to think and feel and see the world around them. And the love that all these people who, who were trying to help them have that they couldn't even recognize.

Yeah, that's very, very powerful. I don't have anything that I could even think to add to that. Let's go back to the pizza store. Pizza shop. You're watching your colleague, what was her name?

Mary Marianne Quinn.

You're watching Marianne pull the croutons out of the Caesar salad and it plants a bug in your mind. Right?

Right.

So how long from then until you've discovered this continuous glucose monitor little contraption?

So only about four or five years. I was a fellow at Boston Children's and I worked in a basic science research lab studying insulin signaling with Morris White. And then I go off and I get my first job as an assistant professor at UPenn. And I'm there and I set up.

So. Okay, so you're at chop actually. Right?

Right.

Yeah. So you're bouncing around between the biggest children's hospitals in the world.

And I set up a lab studying beta cells. And my idea was that I was going to use basic science to advance outcomes for people with type one. And I have this background and a bunch of passion in trying to figure out ways to grow new beta cells in the hope is we'll be able to find some way to do that safely and reliably. And I also have a clinical practice that's focused on type 1 and other endocrine disorders. And along the way, I become very close friends with people who live with Type one, and I start to talk to them and follow them, and I start to meet some of the reps, that is the sales representatives for various companies, including one who herself has type 1 diabetes. This is Natalie Bellini. So she's an amazing person who has type one and she's wearing this device, which is this black hockey puck. It's this Dexcom thingy.

What generation was that?

It was the very first. Wow. And so this is approximately 2,000, maybe seven. And I thought, well, this is amazing because it's. It's obviously a consumer device, it's approved, and then you can give it to patients and they could wear this thing and then they could figure out ways to improve their glucose excursions. And actually, several of my friends went on them and what they discovered was the devices were incredibly frustrating because if you just wear the device and again, a Dexcom or is just one that's a company that's making a continuous glucose monitor. And what they do is they take a probe that goes into your interstitial space, say in your belly. It's a very small needle and it sits in the space. And what it's doing is it's sampling the interstitial fluid, which is the clear fluid that exists in between cells, which roughly correlates to blood glucose, but is delayed by about eight or 10 minutes. And so the device essentially has glucose oxidase, which is an enzyme, and it's stuck onto this platinum wire. It's basically an enzyme on a stick. And so when glucose comes by and it does the enzymatic conversion, it generates a charge which is transmitted down the wire. And the change in the wire charges is transmitted to this hockey puck like device that tells you your glucose. So that's pretty cool. And it blows my mind when I see it working regularly for patients. And my thought is, okay, so we're going to prescribe these for all of our patients and then they're going to figure out how to make their blood glucoses better. But as it turns out, the first generation of CGMs was a dismal failure and the uptake was incredibly, incredibly small in the population of people with type 1 diabetes. And part of the issue is we didn't really know what to do. So when we looked in the toolbox of trying to help people so they could live with type 1 diabetes, we didn't find much other than badgering them to do a better job, you know, oh, you need to check your blood glucose 20 minutes before the meal and give yourself insulin 20 minutes before the meal and do that in a very reliable way so that your blood glucose is normal. But that's not realistic. And for that matter, no one really knows that they're going to eat. So there's a major problem in that, that we live in this fantasy world in medicine where we think people just need to carry out their lives with more precision. And that will be the answer. But the reality is variance is contained in human behavior. It's just what we do. So that idea of badgering people doesn't work. And then maybe it's exercise. So, okay, as it turns out, if you're a marathon runner and you have type 1 diabetes, your diabetes control is much, much better. And part of the mechanism is via this insulin independent glucose uptake into skeletal muscle via AMP kinase. So there's a whole, there's two different pathways whereby glucose gets into skeletal muscle. One is via the insulin dependent pathway. We spoke about that before, that goes to GLUT4. The Insulin Independent pathway is working through exercise and skeletal and work of muscle. And AMP kinase is this amazing enzyme that is sensing the energy status of the cell. And if you alter the energy status of the cell through a tremendous amount of work, you can basically drive a bunch of signals that go to tell the glut 4 to translocate to the membrane of the skeletal muscle. So now you get insulin independent glucose uptake in the skeletal muscle.

So it's still through glut 4, but it comes from inside the cell activation, I assume, of AMPK activating. Ampk sends the GLUT4 transporter up. And in a non athlete, what is the relative difference between insulin dependent and the AMPK driven glucose disposal in the muscle?

I'm not exactly sure, but I can say that if for instance, I take a kid who has type 1 diabetes and we have stable insulin doses, and then they go on like a ski vacation with their parents and the kids are mostly playing video games and hanging out, and then they go off to Vail and they ski for six hours a day. Those kids can require nonstop carbohydrates until their parents figure out that they have a problem and then they end up on insulin doses that are reduced by 2/3. So the effect can be dramatic in normal non exercise associated glucose homeostasis. I think a lot of it is insulin driven. And so as you carry out more and more exercise, you invoke this pathway more and more.

Yeah, it's so interesting. I need to look into this more because I've never. I can't believe it didn't occur to me to look at the patients with type 1 diabetes to answer this question. I've always wondered what the relative difference is in, you know, like, if you're taking metformin, which is activating ampk, and if you're exercising like crazy, you should be able to dispose of glucose with lower and lower insulin levels.

Right.

And so we can obviously measure this. That's right. In a oral glucose tolerance test. The problem is we don't know why, we don't know what it is that's is that they're more sensitive to insulin, which is. That's a two hour discussion on. And if it's which you and I'll have over dinner right after this. Or is it that. No, they're. Each unit of or heterodimer of insulin produces the Same magnitude of GLUT4 translocation, but they're experiencing a benefit of this AMPK version. In other words, how much of the insulin sensitivity is really less about insulin and more about ampk?

I think for people who are very athletic and who are focused on trying to reduce their body fat, it can probably be a huge contribution. And we have these adults who have type 1 diabetes who are down to 20 units of insulin, and a normal 70 kilogram person would be on 60 or 70 units of insulin. So the marathon runners who are thin, of course, they have very thin body habitus, but many of those people are putting in 60, 70, 80 miles a week or on tiny doses of insulin. So again, so we got.

I have a patient, by the way, with type 1 diabetes who uses five units of insulin a day. Wow. He walks six miles a day, minimum, sometimes 10. And he does not really consume carbohydrates outside of vegetables.

And how much body fat.

I've never seen a higher adiponectin and lower leptin in a human I've ever measured. He is a lean, mean machine. Yeah.

So those people are just my heroes. It's so. I'm thrilled to hear about this. So if we're looking in the toolbox, we find like, badgering people to do a better job, maybe exercise, and then like, what else you got? And so I'm looking around and I'm looking at this and I'm sorry, sorry.

Going back to the exercise thing for a moment, do you see a difference in. I don't like the term aerobic, but people know what I mean by aerobic exercise versus strength. Training?

Yeah, I think the people who are doing distance, who are. That they actually have more contribution of this AMPK pathway. And Lori Goodyear has studied this for years and years. She's at the Joslin. And again, this AMPK exercise associated pathway is incredibly potent, but it's all distance. I don't think it's strength.

And then do you think there's a difference between going out and running 10 quarter mile repeats at staggering intensity, where you're burning through glycogen in the muscle versus, you know, so that would only be what, a total of two and a half miles of running versus going out and running six or seven miles at a much lower intensity. Do you think there's a difference between those two?

Yeah, I think there's a huge difference. But what I hear over and over again is the people who are the. The distance athletes. So the people were able to dramatically reduce their total amount of insulin. But again, there's relative debate and this is not well studied. So you'd like to really carry the proper study with high intensity exercise versus very slow, long duration exercise. But this idea of trying to sort of hack the system to reduce the total exposure to insulin and therefore reduce the volatility and the hyperglycemic excursions, that's really exciting. And I suspect that the people like your patient who have down to 8 units of insulin, these people have really cracked the code.

So when did the Dexcom for you? Was it around Gen 4 that it really started to become a real impact? Yeah, the G4 was a special device.

So for me, it wasn't just that we replaced the hockey puck. At least in my life. The transformative thing was learning about Dr. Richard Bernstein in his book.

Do you know Richard well?

I only talk to him on a teleconference. I'm on a low carb physician teleconference that happens once a month. And I talk to him regularly.

Then you got to get me on this. How am I not on this? I'd be very curious to just be a fly on the wall. Is there any chance I can get invited?

Yeah. So it's run by Virta Health and it's focused on type one.

Ton Verta? Yeah. How did I not know about this?

So it's low carb and type one, and it's physicians who are very much interested at the intersection of type 1 and low carb. It's really cool.

I've never met Dr. Bernstein, but I've read his book and I've spoken on the telephone with him. He's Very graciously extended an offer for me to come out to his clinic and spend time. And I would give anything to be able to make that time. I just haven't been able to. But it's safe to say he's kind of the guy who spent more time doing this and has more clinical experience in this than probably anyone else.

And because he did it with himself. Right. It's amazing. He actually got a YSI blood glucose tester and has been using it at home forever. So he's been blood glucose testing before anybody else did. And he had this essential core idea, which was carbohydrates caused blood glucose excursions and that he has the so called rule of small numbers, which says that if you consume more carbs, you need more insulin and therefore there's a greater opportunity to make a mistake. And so if you consume fewer carbs, you will consume less insulin and you'll have fewer mistakes. It's a very simple idea. It's laid out along with a ton of practical tips in his book. He's incredible. He figured this out and we'll link.

To his book, but it's called the Dr. Bernstein so diabetes Diabetes Solution. Yeah, it's a bible. It's like, it's a tome.

And it's for type one and type two and it includes all sorts of pearls, not just on straight diabetes, but also diabetes complications. It's really shocking. And he had. And again, this is like the 11th or 12th edition. He's been doing this for years and years. So he has a private practice. He's in his 80s. He lives in Westchester County, New York and is working out and incredibly healthy. So he figured out that if you avoid carbohydrates and if you give medium and long acting insulin to cover protein and fat and basal metabolic requirements that you could get, blood glucose is very, very close to normal. And he typically prescribes a low carb, high protein diet. It's not low carb, high fat, it's not ketogenic.

What have we learned from Bernstein's experience on how insulinic protein is? Because that's somewhat debatable, right? I mean, clearly proteins stimulate some insulin and certain in vitro studies suggest it can be very insulinogenic. What does the real world experience tell us about that?

In my patients with type 1 diabetes who consume protein and don't cover it with insulin, they can get these massive glucose excursions. And we think in general there's a ratio of around 10 grams of protein to end up being 6 grams of carbohydrate. But the problem is the kinetics are not immediate. So you don't get gluconeogenesis in a matter of seconds. It's delayed over hours. If we had a.

And doesn't it also depend on their nitrogen requirement? So in other words, you could have, which is obviously true with glucose, but you could have two individuals who are similar at the crude metrics. Say each of them gets 40 grams of protein, but one of them has just finished exercising or lifting weights and the other one hasn't. And you're going to presumably see very different glucose responses. Correct.

The vast majority of humans were at homeostasis. And overall, if you look at the USDA requirements, this is suggesting we need to consume 56 grams of protein. And the net result of that is approximately 6 grams of protein that go into metabolism. So, excuse me, seven grams. So there's a net excess that's 49 grams. That ends up being approximately, what is that, 30 grams of carbohydrate. But on the other hand, if you're consuming high protein, if you sit down to a 12 ounce ribeye and it also has fat, which will delay the absorption, the sum total of that could be 80, 100 grams of protein that turns into glucose. That is at this moment, massive slow wave that rises and stays high for much of the evening after you eat it, which could be very frustrating. So a lot of people who had type 1 diabetes think, well, I'm going to do this sort of low carb thing. So instead of eating the pasta, I'm going to have a piece of fish and some vegetables. But there's no carbohydrate. Cool. I don't need to take any insulin. But then you get this weird glucose excursion that comes from the protein. And the essence of the Bernstein method, if you read his book, is to try to cover protein with insulin. And he uses regular insulin, not short acting hemalog or Novolog. And the idea is the regular insulin, which is human insulin, has a peak of onset within approximately an hour or two and it lasts for six to eight hours. And so it roughly, very roughly corresponds with the kinetics of what protein will do to your glucose, glucose. So what's unique about Bernstein is he's using this ancient form of insulin, human, regular human insulin, instead of these very rapid acting analogs because the protein is absorbed and turns into glucose in a delayed fashion.

I've never really understood these rapid onset insulins because they seem to get back to this oscillation problem of, I mean, so the first observation of Bernstein is more carbohydrate means more insulin. More insulin means more vacillation. But now you're introducing another effect which is short acting insulin causes more rapid changes in the glucose, which can more easily result in you making another decision after that amplifies the signal instead of dulls the signal.

Right. So to go back to your analogy of the plane, potentially, what it means is a plane that can much more rapidly gain or lose.

Yeah, yeah.

And you can get into a lot of trouble. And unfortunately, the insulin pump companies and even the insulin companies have advocated an approach that says, look, look, people who live with type 1 diabetes have tough lives. We need to support them, and they should be allowed to eat what they want and they should just cover for it. And the problem is you end up with these crazy oscillations. And the oscillations are associated again with a tremendous burden of illness and this cognitive load and this fear and this anxiety.

And you'll have to forgive my sort of snarkyism, but that's a really wonderful business model if you want to sell more insulin too.

Yeah, exactly. Because you consume. Well, first of all, everybody gets a pump, and then they're. And then they're told that this is the way to feel normal. You're on shots, but you go to pump and then you can just eat what you want. And then, and then, of course, you consume insulin and you gain weight and you need more insulin. So.

Yeah, and I'm not, I am so not the conspiracy guy, like. But I also believe it's important to understand incentives. And I don't think pharma is evil. I think far more good has come from the ability of being able to sell insulin and sell insulin pumps and all these things. I, I really do think these are a net positive. But I also think we have to keep in mind there are modifications that you can make, and obviously you live this with your patients that can give you 80% maybe of the joy that comes from eating. I mean, let's be honest, I think to eat a restricted diet, to eat a diet that is far fewer in carbohydrates, you're giving up some pleasure. There's just no doubt about it. But if you could give up 20% of the pleasure of eating and get 80% more benefit in your health, you know, those are the kind of asymmetric benefits that I think in the long run probably you know, pay off. But, but they're. It's still not easy.

I had to figure this out for myself, and I had seen people do low carb And I didn't really understand it and I just started doing it myself. So I gradually cut back carbohydrates until approximately four years ago when we went low carb as a family and my wife cleared out the pantry. There were no more enriched carbohydrates in our house. But he had teenage girls who were. One was in college and one was going off to college. And like, I can. I can remember the day and I had wanted to do it, she wanted to do it. We just decided to try it. And so we went low carb as a family, and then we've stayed on it ever since. So actually, these days I'm probably ketotic. I wouldn't be surprised if my beta hydroxybutyrate is well above one right now.

So when did you start to. I mean, I guess now that I'm thinking about it. We were probably at the G5 by the time you and I met. And I remember you showing me data, and I really think at the time, your patients averaged about 5.7 in their hemoglobin A1c, which is as normal as normal gets. Yeah.

And part of it, you know, it took me a while to understand the power of this.

And you also noted, by the way, that they had fewer hypoglycemic events than patients who were walking around at 7.

Yes. The incredible thing is that you can reduce the excursions and people have very few lows. And again, I read Bernstein and I also learned of a recent Facebook group which is called type 1 grit T Y P E O N E G R I T. And so that's a group of people who are followers of the Bernstein method. And it's an amazing group of people who are supporting each other. And you see CGM tracings and you see foods that they eat, and you see happy kids or adults, and you might see somebody complaining about their healthcare provider who didn't have a clue about low carb. And it's just sort of a conversation that happens in private amongst people who live with type one or those who are. Who have a loved one. And there's also healthcare providers like me who are part of it. And again, so it took me a while to understand it and to understand its nuance and to start to iterate it. But for me, the real turning point was changing the way I practiced medicine. So the problem with endocrinology is the schedules were so tight and the only way I could see patients was every, you know, 20 minutes or 30 minutes and to try to talk to somebody about Something as complicated as living with type 1 three or four times a year and also renew their prescriptions and go through their labs and document and all this stuff was impossible. And I just decided for my own sanity that I needed to change my practice. And so at the time I had a very small amount of clinical responsibility because I was mostly in the research lab. And I also had administrative responsibility. So what I decided to do was to make sure that when I saw patients, I only saw them at the end of the day. And the idea was I'd see them starting at 4:30 and we would just spend as much time as it took and then I would add it on other patients. But for instance, some endocrinologists will run from room to room to room to room. I only need one room because I'm going to see a patient for an hour and then when we're done, they leave and the new one comes in. I don't need to run back and forth. There's nobody else. So I made a conscious decision that I was going to be more inefficient, that I was going to spend more time with people. It's possible I was going to spend much more time doing clinical work for the few patients that I saw. But I wanted to carry out experiments just to try to determine what sort of impact I could have. And the crux of the idea was if you have limitless resources that you make available to a patient and you really try to listen and understand and support people, could you have transformative outcomes? And fast forward several years. What I've discovered is that some people who medicine is essentially given up on, you know, these teenage kids who have hemoglobin A1Cs of 10 or 12 or 14, who are basically on a super highway to death. You know, these are the people who are going to have their first heart attacks when they're 35, that you can do a lot and help them, and they feel paralyzed and they're looking for somebody who can really understand how difficult it is and to provide a level of comfort and compassion. And sometimes the first five visits you end up talking about almost nothing at all.

But you're establishing a rapport and they get that you're going to be in a different mold than maybe the other endocrinologists they've seen.

And so, you know, I try my hardest, and this is really hard for me because I love to talk, but you know, I try my hardest not to talk and to just ask open ended questions and to be there. And in general I found that If I'm asking questions and allowing them to have the space that we can open up, and ultimately they can begin to acknowledge that it's really difficult. They're looking for new ways, they're eager to try it, but they are distrustful of this idea that I'm just going to sort of give them a short list, like a recipe, and then run away and expect them to do it. So it requires patience. And this is especially true of teenagers who, you know, that feedback loop of giving them information and seeing them act on it, it is delayed by all their growth and development and everything else. And especially with teenagers, it's so important to suspend disbelief and to be there for them in a patient and loving way, even if they can't immediately respond in the way you want.

So we now have in the toolkit of treating patients with type 1 diabetes, we've got exercise, we've got continuous glucose monitoring, we've got carbohydrate restriction. Are there any other apps or technologies or things that you think are paramount to helping, or foods, for that matter, meaning packaged foods that are particularly useful? In other words, if you're a parent and you're listening to this, or if you're a person and you're listening to this, who has type 1 diabetes, and this is all news to you, you're listening to this, and this is totally blowing your mind, what do you need to go out and get to get started?

Well, I mean, CGM is essential.

And I'm assuming, are there any insurance companies that are not covering CGM for type 1?

Plenty. And Jesus Christ. Seriously? Yeah, well, part of it is a huge fraction of people in our country now have these high deductible plans, so they're on the hook for their healthcare expenses. And when their kid is healthy and everyone's healthy, they're good. And all of a sudden, their kid gets diagnosed with type 1 diabetes, and it's like $10,000 a year. Yeah, $10,000.

Right. The insulin cost alone can just kill.

These families and the cgm, so. But CGM is really important. And then in the toolbox, there's a few other key things, but the most important thing is information. So you gotta have Bernstein's Book. You should be following Type one Grit, which is this Facebook group, which, again, which is a wonderful place to learn about low carb. There are wonderful podcasts and Also some terrific YouTube videos talking about the intersection between low carb and Type one. I want to put in a plug for an organization called Low Carb Down Under.

Okay.

Which is really a wonderful group of people. Dr. Rod Taylor in Australia. In Australia, yeah. Dr. Rod Taylor is an amazing character. He's an anesthesiologist in Melbourne and a passion passionate advocate and supporter of all things low carb. And his organization goes around the world doing AV capture of low carb talks and so on YouTube. They have a YouTube channel with over 8 million views on various low carb things, including some terrific talks on low carb by, for instance, Dr. Troy Stapleton, who's a radiologist who got type 1 diabetes himself and figured out how to hack it using low carb.

Where does he live?

He is in Brisbane. He's an amazing person. Very nice. So there's this growing community of low carb nerds who are trying to help people with Type one and again, there's a bunch of different places where it's happening. Another really nice resource is Adam Brown's book which is called Bright Spots and Landmines. And he works for Close Concerns. And he wrote this book essentially as the manual for diabetes that he wish he had been given. And it contains lots of tips and tricks about how to think about living with Type one. And it's from wellness and to exercise, to sleep, all the way to very practical tips around low carb and nutrition and type 1.

How careful does someone with type 1 diabetes need to be if they go on a ketogenic diet? Obviously in patients with a normal pancreas, even those who are somewhat compromised by type 2 diabetes. I'm not aware of any case of keto ketoacidosis.

Right.

Diabetic ketoacidosis, but in patients with type 1 who have no insulin production, that would have to be a real concern, wouldn't it?

Well, I think that there are some interesting intersections in between a hardcore. I'm not talking about generic low carb or low carb high protein, a la the Bernstein method, But let's talk about the people who were trying to get into nutritional ketosis with a beta hydroxybutyrate that hovers around one to two. Well, those people have a couple of unique problems and one is diabetic ketoacidosis, as you mentioned.

Again, for the folks to understand why that's the case, and you or me, even when I'm fasting and I fast for a week at a time, my beta hydroxybutyrate level will reach 6 or 7 millimolar, but it's not going to reach 10 millimolar. It's certainly not going to reach 12 or 14, which is where we Start to see the acidotic changes because eventually that ketone is going to elicit some response from insulin, right? In the person who has no beta cell reserve, that ketone can go unabated.

So prolonged fasting in a person who lives with type 1 diabetes is probably a bad idea because you could get your beta hydroxybutyrate to 6 or 8 or 10 and you could start to feel sick. Another issue is it's a new phenomenon called euglycemic dka, euglycemic diabetic ketoacidosis. And we're seeing this in these sodium glucose co transporter inhibitors, these SGLT2 inhibitors, and it's a very bizarre phenomenon. But in people with type 1 diabetes who go on these sodium glucose co transporter inhibitors, they can get a strange form of DKA where their glucose is not elevated. And it has confounded the field. And there have even been deaths associated with this. There's currently clinical trials and full disclosure, I've been a consultant on one of these programs.

Does this only occur in patients with type 1 diabetes? Or can patients with type 2 diabetes who are the predominant users of the SGLT2 inhibitors also get this euglycemic ketoacidosis?

We think it's mostly type 1s, but it may also be type 2s. And the problem, I think it's probably mostly type 1s. And here's the issue, like, how do you get this? Patients with type 2 can get DKA, but largely it's at new, it's at onset, it's not established disease. The people who have type one who have decided to take these drugs, by the way, this is all off label and I'm not at all advocating it. There are clinical trials and we're trying to develop appropriate safety and monitoring for this. Listeners shouldn't be given free license to go on these things because it's really complicated. But again, if you're on a really potent glucose lowering agent, which is what these SGLT2 inhibitors are, and you have type 1 diabetes and your insulin is infusing from your insulin pump into your belly and the catheter plugs and it stops infusing insulin, then normally you'd look at your CGM and you'd see, okay, my glucose is rising, I must have a problem. But if the glucose lowering agent is essentially dragging all that glucose out into your urine, essentially what, what it does is it's dragging away glucose, which is the primary biomarker of life threatening insulin deficiency. Elevated blood glucose is the primary biomarker of life threatening insulin deficiency for people who live with type one. So when you look at your glucose and you see that it's normal and you're on an SGLT2 inhibitor, it creates a situation of what I would call cognitive dissonance where people just don't understand that they're in trouble. And there may be a delay in between when they had the plug in their catheter or some other interruption of insulin infusion and when they actually end up recognizing it. And so I think that they end up receiving medical care way later. It's also possible that they have elevations in ketones from these SGLT2 inhibitors. The beta hydroxybuty is a little bit higher in the SGLT2 treated population compared to the controls. Okay. So that phenomenon of euglycemic DKA might also extend in rare cases to people with type 1 diabetes who are on nutritional ketosis. And the way I think of it is some of them may have depleted glycogen because they're not fully fat adapted, and many of them will have very little carbohydrate in their intestines because they just don't consume that much carbohydrate. So those people, if they have a plug in their catheter, might not see the same sharp rise in blood glucoses that you normally would, and they might have a delay.

So this is all associated with pump use. In other words, we don't see this in people who are not using a pump.

Well, we also see it in people who forget to take their shots. And oddly enough, people with type 1 diabetes do forget shots on occasion, especially the teenage kids that I've cared for. So.

God, there's so many more things I want to talk about.

Well, one thing I want to just mention is the intersection of nutritional ketosis and hypoglycemic awareness. So there are people who are in hardcore ketosis who have circulating beta hydroxybutyrate or one or two who become completely immune to low blood glucosis. And I had a patient call me up, and he goes, Dr. Jake, guess what my blood sugar is? I said, What? He goes, 25. I said, why are you calling me and not taking carbohydrate? He goes, I feel fine. So he.

What was his bhp?

Oh, like two or three. So he'd done the George Cahill experiment where he had.

Except Cahill subjects were like 6 millimolar, 7 millimolar, 2 or 3 is relatively low to be thriving at. Yeah, 25 milligrams per deciliter. That's barely over 1 millimolar.

And so he has hypoglycemic unawareness. And so to quote Peter Thiel, like, is this a feature or a bug? If it's a feature? Well, he's hypoglycemic unaware, but he's fine. He's cruising around and he had the gumption to call me up if it's a bug. Well, maybe the delta in between his blood glucose when he called me up with a blood glucose of 25 and a fatal low might be relatively small. I have no idea.

There are many other things I want to chat about, but based on some time constraints, I know we need to wrap this up. So maybe we'll have to come back and do a discussion about two other things I wanted to get into, which is sort of the future of this. I certainly remember being involved in the care of patients who got pancreatic transplants. That's obviously a transient solution that often comes accompanied with a kidney transplant. There are certainly beta cell transplants which have really not been that successful, though. It's always one of those things where it's. It seems like it's just a year away from being perfect. There's xenotransplantations of beta cells when you take the beta cells from another animal. Something that's non human that has all of its own problems associated with the immune response. You talked a little bit about stem cells and then of course we've alluded to fully implantable or even non implantable, but fully autonomous pancreases. So that's a whole other topic that would be great to come back and talk about. But I'd like to close on one other question, which is if you were to reflect on everything you've learned in caring for patients with type 2 diabetes, what are the most type 1, sorry, type 1, I'm sorry, type 1 diabetes. What are the most important lessons that would extrapolate to the non diabetic population?

When I look at the cardiovascular outcomes and the weight gain associated with Hyperinsulinemia in type 1, I'm really shocked. And again, I think you have this unique population where you see the insulin that goes into them and you see its direct impact on weight gain. So we know that people consume very high carbohydrate diets and gain a bunch of weight and type 1 diabetes, they're at risk for cardiovascular illness. And to me that just says that there's something about the standard American diet that's making us sick and ultimately we will be at risk for cardiovascular disease. That's the primary thing that humans will die from.

What do you think it is about hyperinsulinemia that seems to drive this? Because this is the thing that I've always found fascinating is that. So when you look at something like. So let's look at the type 2 diabetic cohorts. When you have patients who are using drugs like metformin, which are lower in glucose to achieve better outcomes, versus drugs that raise insulin because the patients with type 2 diabetes still have the ability to make insulin, you can in both of those examples get the same glucose level. But in one patient there's a higher insulin level. Those patients have equal microvascular outcomes, but they have different macrovascular outcomes.

That's right.

Which is a sort of natural experiment to suggest that the insulin is playing a bigger role on the macrovascular disease. The glucose is playing the role in the microvascular disease. Yeah.

And in the case of. Of these SGLT inhibitors, they're the first drugs that have really shown a profound impact on cardiovascular outcomes. This is secondary prevention for cardiovascular disease in people who have already had an event, who also have type 2 diabetes. So empagliflozin is an amazing drug. When reduced the cardiovascular complications by 40% and the drug essentially drags glucose into the urine. And it suggests that circulating insulin values themselves might be in some way contributing to cardiovascular disease. The simple answer is I don't know. There's a lot. There's a rich debate as the mechanism.

Yeah, I mean, do you think it is due to endothelial injury?

Some people claim it's all about the kidney and fluid and the amount of salt retention and something else. But to me, as a basic scientist who grew up idolizing Dr. Cynthia Kenyon and the amazing work that she did in C. Elegans from the Daft Hour complex, those papers suggest that when you make a modest alteration in insulin signaling, the worm lives twice as long. And that fundamental observation has now been borne out in model organism after model organism.

But she did that. I mean, it's tough to. I mean, I'm so familiar with Cynthia's work, so I don't want to bore people with all of my nuance thinking on this, but it's hard to make that exact comparison to us. Right. Because that was a modulation of DAF2 and DAF16. So they were. She was upping FOXO effectively and downing igf. And to get the real step function change in longevity, she had to calorie restrict the worms as well. So there are so many moving pieces in those Models that, I guess. Well, if. Look, if you don't know the answer, that means it's that we've still got some thinking to do on this, but.

I want to go back to your patient, the one you told me about, who's super healthy, who's on six units of insulin. Yeah, I just. I think that those people may be telling us something. He's thin, he's active, he's on very little insulin, and he's quite vigorous. And I just wonder whether carrying out these tricks to try to reduce your circulating insulin could be incredibly beneficial.

Well, part of the reason I love the CGM is it's the best proxy I have for what I don't have, which is an area under the curve of insulin. I'd love to. Some people ask me sometimes, if you could wave a magic wand and have something that doesn't exist, what would it be? And my first answer is a metabolic signature for autophagy. My second answer would be, every night I'd like to go to bed and have a little readout that says, this is the total amount of insulin your pancreas made in the last 24 hours. Can you imagine adding that to the list of my oura ring, the cgm, all the other things I think are really, really driving benefit in terms of health. But to be able to actually know the auc, the area under the curve of insulin produced every day, would be remarkable. And amazingly, someone with type 1 diabetes gets that for free. They just have to look at the syringe and know what they injected.

Yes.

So if there's one thing that that patient with type 1 diabetes has over the rest of us that don't, it's that they can know at the end of the day exactly what their AUC of insulin is. While we can only estimate it tangentially by looking at the things we look at, which are, you know, meaning someone like me can look at average glucose and standard deviation of glucose and just try to minimize those as an indirect proxy for that AUC of insulin.

These people are really amazing, and the most successful are so dialed into their physiology, they're doing quantified self before. Before it was even a term.

Yeah, exactly. Well, on that note, Jake, I know you're super busy here in San Diego today, and so I really appreciate you making the time to come over here and share a little bit of your wisdom and your insights. We'll have to do this again at some point because as I said, there's so many of the things that I want to talk about. And I'm sure there are other people listening to this who do as well. So with that said, until next time and thank you.

It's an honor. I really love your show. I've been listening every week.

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