#1643 Grand Rounds: Stephen E. Gitelman, MD
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A conversation with Dr. Steve Gittleman on predicting, preventing, and treating type 1 diabetes—covering genetics, environmental triggers, screening, and emerging therapies like teplizumab to delay or alter disease progression.
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Scott Benner 0:00
Welcome back, friends. You are listening to the Juicebox Podcast.
Dr Steve Gittleman 0:13
I'm Dr Steve Gittleman. I direct the children's Diabetes Program at the University of California at San Francisco. In this role, I help manage patients in the clinic, and then I spend a lot of my time in the research world trying to better understand why type one happens, and how we can alter that natural course of progression to clinical diabetes.
Scott Benner 0:36
My grand rounds series was designed by listeners to tell doctors what they need, and it also helps you to understand what to ask for. There's a mental wellness series that addresses the emotional side of diabetes and practical ways to stay balanced. And when we talk about GLP medications, well we'll break down what they are, how they may help you, and if they fit into your diabetes management plan. What do these three things have in common? They're all available at Juicebox podcast.com up in the menu. I know it can be hard to find these things in a podcast app, so we've collected them all for you at Juicebox podcast.com Please don't forget that nothing you hear on the Juicebox podcast should be considered advice medical or otherwise. Always consult a physician before making any changes to your healthcare plan or becoming bold with insulin. The episode you're about to listen to was sponsored by touched by type one. Go check them out right now on Facebook, Instagram, and of course, at touched by type one.org, check out that Programs tab when you get to the website to see all the great things that they're doing for people living with type one diabetes touched by type one.org I'd like to thank the ever since 365 for sponsoring this episode of The Juicebox podcast, and remind you that if you want the only sensor that gets inserted once a year and not every 14 days you want the ever since CGM, ever since cgm.com/juicebox one year, one CGM. Today's episode is sponsored by the tandem mobi system with control iq plus technology, if you are looking for the only system with auto Bolus, multiple wear options and full control from your personal iPhone you're looking for tandems, newest pump and algorithm. Use my link to support the podcast tandem diabetes.com/juicebox, check it out.
Dr Steve Gittleman 2:33
I'm Dr Steve get I direct the children's Diabetes Program at the University of California at San Francisco. In this role, I help manage patients in the clinic, and then I spend a lot of my time in the research world trying to better understand why type one happens and how we can alter that natural course of progression to clinical diabetes.
Scott Benner 2:54
Awesome. I would like to understand a little bit about your background first, so I'm going to take you back a little farther than people usually do when you're in high school. What do you think you think you want to be when
Dr Steve Gittleman 3:02
you grow up? Well, yeah, I think the seeds for me were planted even earlier. I say that just because of issues within my family, you know, I think a lot of people that end up in a diabetes career have both personal and professional motivators. So for me, what I heard about as a child growing up was my maternal grandfather, and he developed type one shortly after the discovery of insulin. He was kind of held out in our family as just, you know, one of those miracle experiences he lived many decades. His Life wasn't easy. I heard how he had to take a train from upstate New York to Boston to pick up his regular allotments of insulin, and how my grandmother modified her recipes to make them more appropriate for someone with diabetes. So I heard about his life then I watched as others on both sides of my family developed issues, either with type one or other autoimmune issues. So you know, I saw firsthand how that impacted their lives. My next intersection with the whole challenge was my father happened to work as an adult kidney specialist at the University of North Carolina, where I went to medical school, and I was very surprised as a medical student, to see young adults who are his patients who had kidney failure. You know, I used to nudge him. Why aren't your patients doing better? This was, you know, a different era before we really understood how important it was to keep blood sugars in a near target range to prevent these things. But he basically gave me a nudge and just said, you know, why don't you try and help the field? You know? Why? Why is this happening? Can't we better manage diabetes? I think you could prevent all this if you really knew what was going on. So I think. That was, that was the gauntlet, uh, threw it down to me at an early, early
Scott Benner 5:04
age. And so does that lead you to endocrinology? Then that idea?
Dr Steve Gittleman 5:10
Yeah, so in high school, you know, I was interested in science and biology and intrigued by what he was doing as a physician scientist, I think the two things I kept in the back of my mind as I was heading off to college was, gosh, I think I like biology. Probably want to go into medicine, but, man, I really enjoy summer camp. I want to make sure I can stay involved as a camp counselor and be outside and play. So with those two primary goals, you know, frame shifting down many years of training. You know, diabetes, you know there was that personal connection and just scientific curiosity, yeah, but then I spend a lot of my time at diabetes camp every summer, and so somehow, I guess those high school goals came to pass.
Scott Benner 5:59
Excellent. Hey, what other autoimmune issues run through your family?
Dr Steve Gittleman 6:04
Yeah, it turns out I have a grandparent with rheumatoid arthritis. There's thyroid issues, others with type one. I think those are the main, main issues of note.
Scott Benner 6:15
And how about for yourself, or any of your FA Do you have children?
Dr Steve Gittleman 6:19
Maybe. Yeah, yeah. So I do not have type one, and I always preface this by saying yet, because, you know, I have those genetic underpinnings, and this can happen at any age, less likely as you get older, I have three children, and they've all been screened for their risk repeatedly over time and have tested negative to date, but you know, we continue to watch them closely over time.
Scott Benner 6:46
Sure. Well, I'll knock on something for you. Thank you. Yeah, yeah, no, of course. So Okay, right now today, you're a practicing physician, but you also consider yourself, just like your father, you're also involved in research, so I feel like maybe we want to talk more about the research aspect of what you're doing first, how does that begin? And how long ago did you start? I don't know if you have a lab or what you do, but I'd like to understand how you're set up and what your goals are.
Dr Steve Gittleman 7:12
Yeah, along the way in my training, I did do a lot of laboratory work, and it was not in diabetes, specifically, a great experience. I think I got fairly deep into that and missed, you know, more personal connections with patients. So I shifted gears and moved from that lab based existence to more clinical research. You know, I think the question that many of us working in type one have continued to ask over time is, why can't we screen and predict who's at risk and stop this from happening? Yeah, I think it's an exciting time. It's, you know, it's very natural question to ask. You would think we would have answered this many decades ago. You know, I think we're making nice inroads in at least the prediction side, and then if you can find people at risk, Boy, wouldn't it be nice if we could delay or prevent diabetes from happening? So I think finally, we have at least one therapy that's that's doing that.
Speaker 1 8:16
Which do you think is, is the answer in terms of therapies, or
Scott Benner 8:21
you said you think you have a therapy. I mean, there's a, I mean, there's a couple of them out there, right? But is there one that you that you like the best
Dr Steve Gittleman 8:29
when we talk about altering the course of type one? I think there been, you know, you can intervene, really, in three different arenas. And you probably talk about these widely on your your podcast. You could come in before clinical disease try and screen and predict and try and prevent it from happening. You could come in shortly after diagnosis and try and extend what we call the honeymoon phase. At the time of diagnosis, you may have up to 40% of your insulin producing beta cells. Beta cells still present. So extending that honeymoon can make a big difference clinically. And then for people with longer standing type one, you know, I think the question is, why can't we replace the missing beta cells? So it's kind of, you know, those, those three main places to intervene, prevention, preservation, replacement. So if I was going to make a t shirt for my research team, I think that would be the that would be the tagline, yeah, yeah, that's the mantra. You know, I don't work much on the replacement side of things. I follow very closely. I think that's very exciting. But I do think a lot of what we learn on the prevention and preservation side may apply to the replacement side. So I think there's nice conversation between investigators that work across those three phases to inform and support and guide each other.
Scott Benner 9:55
How do you describe what you're most focused on? Which of those three phases? Interests you the most, and where are you having the most success?
Dr Steve Gittleman 10:04
Yeah, yeah. So, you know, as a pediatrician, I think a lot of our focus is on prevention. Prevention trials are different, difficult to conduct, and so what's happened over time is a lot of times our proven ground is come in with something shortly after diagnosis to try and extend the honeymoon. And if it's safe and effective there, it's something that we can consider taking into the at risk population and maybe think about using in replacement strategies.
Scott Benner 10:37
Okay, let me make sure I understand. So if you had a mechanism to extend the honeymoon and it was safe, then maybe you could use it prophylactically in high risk people. And I guess you'd just have to, if they didn't get type one, you'd say, I guess it worked. The entire thing, as you're talking about it, is so predicated on finding these people, getting them to be interested in helping over long term, not being able to really promise them anything that part of it seems incredibly frustrating to me, even as you're just starting to as you're starting to explain it, can you talk about how difficult it is to find the people to even work with?
Dr Steve Gittleman 11:15
Yeah, I think that's a great question. So it kind of takes us back to, you know, screening strategies, which we've been actively working on around the world for several decades now. And you know our initial focus has been on families where someone already has type one, because we know just from studying family history that they're 10 to 15 fold higher risk. The unaffected family members are 10 to 15 fold higher risk for eventually developing type one compared to the general population. You know, we've looked to try and better understand genetics. The genetics of type one is very complicated. A lot of it is driven by genes that determine self versus non self, but there are over 50 other regions in the genome that are involved. So genetics alone is tricky to use as a predictor. In and of itself, we think that your risk for developing type one is driven by a combination of both genetics and environmental triggers. It's even harder to prove genetic or environmental triggers. You know, we all face such a myriad of different things, I think we have some good leads there, and we could talk more about that. But practically speaking, I think one of the big breakthroughs was screening for an immune measure called Auto antibodies. And we don't think the auto antibodies are causing the destruction of the beta cells, but we think that they're a signal that the immune system has been turned on and is actively targeting the beta cells, and so we can measure now up to five of these different markers in the bloodstream. And I think what we've learned is if you have two or more of these markers, eventually you're very likely to develop type one diabetes. So the first part of our predictive algorithm is really looking at that immune marker. The other piece that we use is, if you're moving down a pathway towards type one, sooner or later, you'd expect your metabolism to start to shift. And so usually this is not something someone's going to notice clinically, you know, with the classic signs and symptoms of nuance of diabetes, but there's subtle increases in blood sugar. And so we can do a stress test on the pancreas, the beta cell, and do an oral glucose tolerance test, much as much like what is done during pregnancy to screen for diabetes, and so we can start to see mildly elevated blood sugars. That tell us, not only is the immune system turned on, but the pancreas is starting to be challenged and not functioning fully normally. And so, you know, we now break these, these steps into what we call stages. So stage one, two or more auto antibodies, we now call that the onset of type one. Biochemically, blood sugars are normal. You're asymptomatic, but eventually we think you'll move to clinical diabetes and need insulin. Stage two is the combination of the immunologic activation, the antibodies, plus the subtle change in blood sugars, we call that stage two, and then stage three is what we used to call nuance at type one. That's when your blood sugars are elevated. You need to initiate supplemental insulin therapy, but you still have those that under current of beta cell function.
Scott Benner 14:40
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Dr Steve Gittleman 17:01
I think this is, you know, one very challenging aspect of all the work we do. And I should say that all this work is funded, you know, in in larger research teams, the National Institutes of Health has been a tremendous funder of this breakthrough, T 1d has been very helpful their international organizations in Europe and Australia all trying to better understand this. And you know, we compare notes and work closely together. There have been lots of interesting studies into this question, and a lot of it's based on epidemiologic observations. So for instance, a lot of interest in early feeding practice. Can breastfeeding prevent the development of type one? Can avoidance of cow's milk formulas prevent the development of diabetes? You know, we see these interesting observations and studies and populations that support these notions, but we don't really know for sure, unless we do kind of a classical clinical trial, you know, what we'd call a randomized perspective, placebo controlled study to answer it. And for the milk question, it was a really nice study called trigger that was conducted in patients in many places in the world. It didn't work. And so I think the prevailing thought is, well, there are two prevailing thoughts. You know, I think one is maybe the beta cell just isn't a very robust cell and doesn't handle stress very well. So maybe it's a series of different challenges over time, whether it's different feeding issues, whether it's different viral exposures over time, just some of that non specific inflammation and challenge to the beta cell. It catches up to it over time, and it just can't withstand those, those challenges, the inflammation and and other aspects, and it fades, and you don't have enough there to sustain your blood sugar control, right? I think the other issue that's been at the forefront of thought for quite a while is maybe, you know, there's a lot of lot of interesting observations that suggest virus is a culprit and different infections. You know, most of the infections have been dropping over time because of vaccination, but viruses have been a challenge. Highest risk for for type one is as you move away from the equator towards the poles. If you move from a region of low risk, say, you know Cairo to Helsinki in Finland, which is the highest risk in the world, you assume that risk in the region you've moved to, there's a seasonality to type one presentations. There's kind of clusters outbreaks, and certain locales where we see type one. So it starts to suggest, you know, infection and maybe virus is part of this. And there are studies suggesting that particular viruses may. A way to home to and invade the beta cell itself and cause destruction. One amazing development will be if we can define particular virus or types of viruses that do this and then vaccinate against them early in life, and just at a very early stage, eliminate risk for progression to type. One sure, a lot of work going on in this area. So I'm, I'm not doing it full justice, because it's, it's complicated, and it's, it's actively evolving, but, but I think you have the gist of it.
Scott Benner 20:32
No, I do. My most of my daughter had Hand, Foot Mouth before she was diagnosed, and at some point, Francisco Leon from prevention bio, who, I guess they eventually sold their their drug off to Sanofi, right? It's to miss a Plov now. Is that what it is? When he was on the podcast, he talked about his idea of like, I'd love to be able to vaccinate for Coxsackie, because I think if we stop kids from getting Coxsackie, we might stop kids from getting type one diabetes. And he seemed very passionate about that, that specific idea, I feel like that's what you're saying here too. Is that there's it's so interesting, like, as you move away from the poles, you said, away from the equator, excuse me, towards the poles. How many people come on here, and while they're telling their story, I don't think it's of any surprise. Many people are very captured with the desire to understand why they or their child got type one. And you know, as they're speaking, you can almost after you do it long enough, you can almost just jump to it and go, Hey, are you know? Are you English or you know, is your background? Are you Scottish? Are you from this part of the country where, you know, like you you're talking to somebody from America, and you realize, like, they're from Minnesota, and their their lineage goes right back over to, you know, Scandinavian countries. And there's a lot of through lines there that I've seen just from talking to people over and over again. It made me feel like kind of going back to my first question about, like, how do you possibly get all these people to do this work. I was thinking like, Would it be easier to just give everyone a survey and ask them all the things you need to know? And at the end, the last question is, do you have type one diabetes? Because that I keep thinking like, I mean, how old are you, sir, 6767 you've been at this a while. I imagine I have indeed, yes, yeah. How do we take what's in your head, like, your lifetime worth of experience and layered on top of somebody else's so that we can continue to, you know, to move forward and not just, like, not have the things that you know, those little aha moments that you've had? How do we not let them disappear so that we can actually get to an answer? I mean, that's a big question, but,
Dr Steve Gittleman 22:42
yeah, you asked a few questions, important questions in there, you know, I think part of this is, you know, the scientific process, you know, we study, we publish, we critique, we're intellectually honest with each other. We try and build on, you know, any positive study to move things forward, we try and learn from anything that didn't work. If it didn't work, why didn't it work? You know, we just stand on the shoulders of the people that came before us. So it's, you know, I think there, there's some issues in life, some diseases that are just simpler and, you know, we have the answer and we're on to other things. You know, gosh, penicillin will treat strep throat. You know, a week or two of treatment, you don't look back. Type One is a complicated issue. You know, simplest terms, it's selective destruction of a single cell type. But the why of it? You know, it's not a single answer. There's not a single gene, not a single environmental trigger, likely, not a single aspect of the immune system. But it's this complex stew of things that we have to disentangle to move things forward.
Scott Benner 23:55
Because if you consider, I mean, everything you've brought up, and even everything that I've seen over the years, like, if it's, you know, there's some environmental and some, you know, I mean, I can't tell you how many people have come on here and said, like, I had a car accident, then I got type one diabetes, or, like, you know, like I had a very traumatic event, somebody died, and then it happened. There's some people who think that trauma started. I'm pretty certain my daughter's Coxsackie is the impetus. But of course, if you look back through my my wife's family, there's a ton of autoimmune stuff with those people. They're, you know, English and Irish lineage. There's things that now, in hindsight, I can say like, Oh, that makes sense. My wife has thyroid issues. So does my son. I'm adopted, so we don't have any idea of, like, what I bring to the mix, right? But I can tell you that I've been anemic through my life, like there's sometimes you start interviewing people, talk to a mom, and then she tells you about her family's background and the husband's family background. And I just initially think, like, oh my god, I bet you three of her kids are gonna have an autoimmune issue. And an hour later into the conversation, they all do. And I just want, I don't know if I've talked myself out of my question. I. Don't know. Like, I feel like everything that's being gathered it all makes a ton of sense, but I see what you're saying that. Like, why would like, I guess the question would be, like, why, if I have a family of six people and they all are living in the same house and all experience the same death of a person, or we're in the same car accident, why does one of them get type one and not the other? Like, that's the real question, right? Like, it's why you and not me.
Dr Steve Gittleman 25:23
Yeah, yeah. I mean, I, I'm the father of twins. They're not identical twins. But if you study identical twins, that's in some ways, kind of ground zero for genetics. You know, if twin a has type one diabetes, what happens to identical twin B and the classic observations would say, Well, maybe 30 to 50% of those unaffected twins will eventually develop type one. It turns out, if we follow the unaffected twin long enough, like you know, 567, decades, eventually, twin B does develop type one. It is intriguing that the timing is very different. The nature is very different from one individual to another. And, you know, although twins grow up in a similar environment, they diverge their genetics. You know, it's kind of a misnomer that all aspects of the genome are the same between identical twins. You know, the immune system has very complex rearrangements over time. But it just tells you, you know, genetics alone isn't the answer, and we just need to know more about those environmental triggers. You know, there's kind of parallel worlds that we look constantly across that, you know other other complex diseases in in our human experience that are this tricky interplay between genetics environmental triggers, right? So I think some of the best studies that are being done, such as the the environmental determinants of diabetes and youth, the Teddy network, some of the efforts in Scandinavia, they're trying prospectively in life, to collect all biologic samples from a given individual at different periods over time and careful histories and surveys and things, and then go back and try and link infections and life experiences to changes in the immune response and changes in metabolism and risk for progression to type one. So I think the right stays are being done. It just takes a lot of people and careful analysis and reassessment over time to put the pieces together. I'll make one other comment is, you know, I think a lot of the focus is you're kind of alluding to is people of Northern European ancestry, type one happens, you know, in almost any race ethnicity, it's increasing where it's being studied. The incidence is increasing in different places around the world. In the US, it's increasing, probably at a higher rate in those of Latino ancestry, we're just starting to understand some of the issues with type one, for instance, in Africa, where we know clinically that people look like they have type one with loss of beta cells, but the process may be very different. We talk about type one is, if it's one entity, but we're starting to realize that, you know, maybe there's subtypes. Maybe there's, you know, different pathways, different triggers, different processes, that result in this n clinical picture where, gosh, you don't have enough beta cell function and you have to take supplemental insulin. Yeah, probably the more I talk, the grayer it all sounds.
Scott Benner 28:43
This is where the conversation is really though, because if I stop and look back at all the different things that I've spoken to people about, people who come on and talk about, I don't know, they had hives, and then they took an injectable and the hives went away. Like, isn't there something to learn from that? Like, isn't there something to learn from how GLP medications are impacting people right now, you know, and their inflammation, for example, is there not something to be learned from isn't all of this going to, in the end, be somehow connected? I think this podcast lets me have these kind of big conversations we've I obviously have no specific training. I don't understand any of this. I'm just the person in the middle who, luckily or unluckily, gets to have a lot of conversations with a lot of people with autoimmune issues. And like, you know, one that I bring up a lot that started to shock me, but stopped shocking me now is the amount of people who will say that they have a bipolar person in their family line, like the amount of people I talk to have type one diabetes, who are like, Oh, my uncle's bipolar, my aunt's bipolar, my grandmother was bipolar. Like, it's overwhelming. How many people bring that up? It's overwhelming. How many people with type one diabetes talk about anxiety in their families? This many people can't have anxiety. Like, and is that all inflammation related? Like, are all these things somehow tangentially to. Touching each other, and is the key to understanding the big picture, understanding little bits of all of the pictures. I keep sitting here thinking like, you know, I had this conversation with this researcher once who he thought that covid was great for research because he said he thought it forced labs to start sharing with each other more. And then I had another person come in here recently who said that they think that AI is going to be one of the ways that they can get through all this information, maybe more judiciously otherwise. Aren't you just waiting for some happy accident? Do you know what I mean for you know what I'm saying?
Dr Steve Gittleman 30:37
Yeah, yeah, you again, raised a couple of very interesting issues for me to comment on. Please take the guest prerogative and selectively and address one or two of them, because they're all all great conversation points that we could spend a lot of please. Please. You know, how do you pull all these different observations together, or any kind of unifying hypotheses that we could use and capitalize on and think about intervening to alter the course. So, you know, these are hard hypotheses to prove and act on, but I'll just, I'll throw two of them out there. One is obesity and the accelerator hypothesis, and the other is what's called the hygiene hypothesis. And you know, these probably have been talked about in other podcasts, and I'll just try and succinctly mention them, and then I want to talk some about things that have been successful, and they give us hope that we can alter the course of this, even if we don't fully have all the pieces of the puzzle. So the accelerated hypothesis suggests that, gosh, if you're overweight or obese, that kind of starts to look like risk for type two. Your pancreas has to work harder, secrete more insulin. You become resistant to insulin, and in fact, you know those at risk and progressing to type one, there's a high chance in this day and age that you will be overweight or obese. So maybe that is an additional stress and strain in someone who's at risk for progressing. They might progress faster to stage three or nuance at diabetes. So you would think, you know, maybe if we treated obesity earlier in the in the course of life, maybe we could lower the risk. We haven't done that study but, but it is a way forward the hygiene hypothesis. It'll take me a minute to set this one up, please. I'll just tell you that full family disclosure, my wife is a children's infectious disease specialist, and of course, the goal in her world is, let's minimize risk for infection, and so in a world now where we're very careful with antibiotic use and Purell and avoiding infections and exposures and using vaccines widely, it's great for minimizing risk for infection, And I am not in any way bashing vaccines in the discussion today. I don't think they have any role in initiating autoimmunity, so I'll just get that out there. But maybe by lowering risk for infection, we're increasing risk for autoimmunity, and that maybe some of those early exposures and infections that were common in prior decades would were actually lowering risk for autoimmunity. So the tension in our family is, you know, if food falls on the floor, I'm happy for the kids to pick it up and eat it, and she's horrified. And I'm being a little silly here, but you get the idea that maybe in a more sterile world, we've increased our risk for autoimmunity. The risk is increasing, not just for type one, but for all autoimmune conditions.
Scott Benner 33:48
Yeah, what's that? George Carlin bit, where he says, When he grew up, they used to swim in the in the East River, and everybody was healthy as a horse, and that river was disgusting. I take your point. So as we get more I guess, adept at keeping everything clean. We're not giving our bodies opportunities to have small, little, conquerable infections and germs that it can learn how to deal with. And therefore, you've sheltered your immune system, and then all of a sudden, you slam it with something, and it doesn't know how to fight back at all, and boom. You think the beta cells. It's po I think I heard you say earlier, maybe the beta cells are just a little more easier to damage, maybe, or less able to like, I don't know. I know. I forget how you put it exactly, but it's, it's odd, because Steve, I feel like it stuck with me, but then all your words left me. But what was it you said that it's possible the beta cells are be less resilient. Less resilient, okay,
Dr Steve Gittleman 34:41
you cut your skin. Gosh, it'll repair beautifully many times over and On you go. But maybe beta cells, they don't regenerate very well. They don't handle stress very well. They're just not a very robust, resilient cell type, yeah, yeah, but I don't want to leave people. Are feeling hopeless, because we actually have had some very exciting results with interventions. If you want, I can train, you know, give the view from 10,000 feet on where those stand and where I see that going.
Scott Benner 35:14
Yeah, no, well, first of all, I don't see your conversation is feeling sad at all. I It's incredibly interesting. I'm again, Steve, you don't know me. I barely graduated from high school. I have no I did not go to college, and yet, like just making this podcast, I think, has allowed me to just hear people's stories in a different way, maybe because I don't have any preconceived notions, or I don't really even have the ability to talk down to anybody. I don't have enough education to even do that. The odd little things that I've seen along the way, I'll give you one from my personal experience, I'm maybe two years into using a GLP medication that I only used for weight. That's why I was using it. I've lost 70 pounds. Wow. I weigh about 166 pounds today. I think I started at 236 Wow. Congratulations. Thank you very much. I had been anemic a lot of my life. No bleeding, no like, I just anemic, and it caught up to me in my adult years, to the point where I would have to get iron infusions just to, like, exist, because my ferritin would go down into single digits sometimes, and I couldn't function. I have not needed an iron infusion since I started using a GLP medication, and my ferritin stays up now. Now simple like, guess maybe my digestion works better, and my food is actually having time to be processed differently, and I'm actually getting the iron out of my food and I wasn't before. I don't know if that's the reason. That's my guess, but what an interesting thing to learn. You know what I mean, like an unexpected thing to learn. Like, how crazy is it about how many women who couldn't get pregnant their whole lives, who believe they have PCOS, for example, went on a GLP and then got pregnant? Those are the little places where I think, like, don't ignore what that means around inflammation, or what it could possibly mean around inflammation. There's this documentary, I think it's just on Netflix. I have no idea how valuable it is or not, but there's this person in it that tells this story. It's about gut biome, the documentary, Ah, yep. And she talks about how she took, you know, the details of it, I think probably would skeeve people out, right? But she took, you know, she she seeded her gut with somebody else's fecal matter. I don't know the technical aspects of how this works, but she did it you're doing well, no, thank you. She did it from either a boyfriend or a brother, and she developed the person's acne. So she had never had acne her entire life. She seated herself with this person's and then the person has acne, and she got acne, so she thought, well, I'll change to the other person. She's a change to the brother, or change to the boyfriend. I forget what the order was. And then that person is depressed. And she'd never had depression in her life, but developed depression when she did it. And I thought, like, that's like, worth remembering. Like, I don't know what to make of that. Do you understand? Like, I'd be a terrible scientist, Steve. I'm already bored with the idea. I'm like, That's a great idea. Someone should do something with that. But like, I wouldn't be good at digging through the details of it, but I think somewhere between ladies with PCOS having kids, and guys not being anemic anymore, and this gut seeding, and people with type one, and I feel like glps being used with people with type one are going to teach us a lot over the next decade. And I'm so excited to find out what those things are going to be. You know, injectables for allergies and like, what are they quelling in the immune system? Like, what is there to take out of that? Like, it feels to me like there are little bits of all these things that will someday, I don't know. I feel like someday you're gonna load all these into your personal computer, Steve, and ask it to make sense of all of it. It's gonna spit the answer back out. And I just, I wonder how long that's gonna take, but I'm excited for people like you to figure it out. I want you. Are you paying attention to AI, like, or is that like, yeah,
Dr Steve Gittleman 39:07
yeah. No, absolutely, absolutely. And you know, there is so much information that we're collecting, but it is hard to know how to best sift through it, and the data sets get larger and larger for all this. So I agree with everything you're saying. It kind of feels like, boy, they're important breadcrumbs in and around us. How what we follow, and you know we gonna Is there a meaningful end along that path?
Scott Benner 39:35
Yes. So yeah, go ahead. Your 10,000 foot view of it, please. Yeah.
Dr Steve Gittleman 39:40
You know, we talked about being able to screen and predict, I will tell you, up until 2018 there had been a number of very well conducted prevention trials and those at risk for type one, you know, they were supported by these epidemiologic observations. We've been talking about, the interventions were tested in animal models of type one of which, they're not too many and too many good ones, unfortunately and oftentimes. There's a pilot study that suggested, hey, I think this is going to work. The long and short of all those studies up until that point was we could identify people at risk. None of the treatments worked. We were frustrated, the field basically shifted to the idea that, why don't we focus on people with new onset type one, where we again, we could see if we could find something safe and effective there, and if it worked, then we could bring that into prevention. Okay, I will tell you, as we're talking today, there are actually 11 different therapies that have extended the honeymoon now, and I'm talking about larger, what we call phase two or higher level studies, placebo controlled, well powered, you know, with a reasonable number of people, one of those has been well evaluated at stage two. So moving from people with nuance of diabetes, where it extended the honeymoon safe and effective, to looking at people at high risk at stage two, and that's the drug you mentioned earlier, called teplizumab, that's the first prevention trial that worked. We can talk through the details. We probably don't have time for all
Scott Benner 41:21
that, but Steve, first of all, I make a podcast. I have nothing but time. We're only on your schedule. Don't worry about that. But the second thing here is, I'm going to ask you a question if you're not comfortable answering. Because I'm going to ask you to just kind of guess. But I have been wondering for years why Sanofi would pay $3 billion for a drug that is so hard to administer, and I can only come up with that. They must feel like something else is going to come from it at some point. Is that a fair guess on my point? Or do you have a thought about it? That's a lot of money to buy a drug? Yeah.
Dr Steve Gittleman 41:55
I mean, I'm not a business person. I'm a Yeah. But you know, in the history of man, the only other approved therapy for type one is insulin, you know, that's replacing the missing component, the missing hormone. It's not getting it. The underlying root cause of the problem teplicit Mab is, you know, a type of immune therapy called a monoclonal antibody. It targets T cells, which we think is a very important part of that immune infiltration and destruction of beta cells. So it's getting more at the root cause of things. So, you know, I think, you know, we've been tremendously excited that this, after years of development, it's getting a toehold, and it's basically, first of all, I think it's showing we know what we're doing here. Here is a therapy that can delay, if not, you know, prevent, until the end of time, the development type one, it doesn't work for everybody. You've mentioned the challenges in giving the medication, and there are a number of questions we can ask based on the success, but, you know, I think we have to mark the moment and realize, wow, so we can do this. Where shall I go with the discussion from here? Let me talk a little bit about some of the aspects of duplicit map and where I see it going and and then kind of bigger picture, about therapies. Thank you. So just to kind of summarize what success looks like at this point in time. So the studies to date, you know, it was one prevention trial. It was about 76 people. The average delay in the onset of type one was two to three years in the group that got the drug versus those that were in a placebo group, some of those people who got the drug have now gone over 10 years without developing type one. The treatment in the trial was daily IV infusion of the medication in an outpatient setting for 14 days and then stopping nothing, no further therapy. The people that are having that long, lasting response. It's a little over a third of those who got the drug. You know, we can look at this glass, half full, half empty. Not everyone responds. It would be nice to know up front. Can we predict who's going to have that super extended response? Or could we know shortly after they've gotten the drug, how the immune system's changed? We're not there yet. We're working on, I think we have some good leads.
Scott Benner 44:29
Did they have any other auto immune benefits other than not getting type one? They get sick less often, anything like tangible
Dr Steve Gittleman 44:40
you know there, there's certainly occasionally people that have other concurrent autoimmune issues, and I don't think there have been enough for us to really know if it alters the course or risk for other autoimmune conditions, the main other things that run with type one thyroid disease and maybe up to 20% Celiac disease, maybe in five to 8% not clear that any of those other conditions are impacted by this. Okay, you would also wonder, well, this is great. How can we build on this response and get an even better response? One of the considerations is maybe we give a second course of this sometime down the road, another 14 day. Course, it could be at a set time interval, like six or 12 months later, it could be following the immune and metabolic response and coming in if it starts to slip. This has only been used in eight and older. And as I mentioned, I think at the top, the incidence of type one is increasing, particularly in younger children, or it's increasing at a rate of three to 5% per year for those under age six. So it would be great if we get these therapies into younger children, and we actually have fully enrolled a study now for children under eight to look at the safety and efficacy in that age group. The idea of simplifying the regimen, as you mentioned, it's not the world's most convenient thing to have to get 14 daily doses and disrupt your life and spend your week and weekends with us. So ultimately, someone has to explore a different therapeutic protocol. And I'll just leave it at that. You could wonder if this could work even earlier in the disease process. I mentioned we used it at stage two, that highest risk point, but maybe if we came in earlier at stage one, it could work even better. I also mentioned that we have 1111, treatments that look very promising in new onset, really duplicit maps, the main one it's gotten. You know this notoriety because we've conducted a stage two study with it, but you could think about any of those other therapies that have worked at stage pre new onset, and move them upstream into Stage Two or stage one, and evaluate them. And those would be the things you know, if they worked by different mechanisms, if you're thinking about combinations, maybe use to place a map plus one of those as a way to really get an additive or synergistic response. So, you know, for me, I think we're, we're at the end of the beginning. You know, it's super exciting that the policeman has worked. You know that that idea that we learn from what we've done in the past and try and build on it? I mean, now's our time. I'll just tell you one other thing you mentioned. I don't know if you you stated as positive things from covid. One thing that we learned from covid was we were conducting a teplicit Bab study during covid, and so a lot of studies were stopped. You know, because of the risk of immune therapy during covid, we don't think of this drug as immunosuppressive. We think of it is immunomodulatory. We give it for a brief period of time, it resets the immune response. It doesn't require chronic therapy. And so we're very keen to continue the studies during covid in part to evaluate its safety. And sure enough, in the trial, the people who got to please med were not at higher risk for covid or severe covid, or, you know, required hospitalization or treatment for covid, it occurred in an even likelihood between the drug treated and the placebo group. So we learned a lot about just kind of the nature of this therapy, kind of the thoughts of using it moving forward. Moving forward, right?
Scott Benner 48:43
That's interesting. If you feel like you've said everything you I mean, obviously I think you could probably talk for another year about this, but if you feel like we've buttoned that up nicely, Can I shift you a little bit into into your practice and ask you a couple of questions? Okay, yeah, that's awesome. Thank you. I appreciate it. I know it's a big change I'd like to throw out to you an episode or two that I've done in the last couple of years that sticks with me over and over again, right? So I talked to the mother of a young girl who has type one diabetes. She's in her teens, and the mom has PCOS and had a weight struggle that she eliminated with GLP medication. She notices the daughter, who's had type one for many years, of three, four years, type one diabetes, using, you know, 50 units a day, like, you know, has the genetic markers. She's type one, et cetera, the daughter is starting to gain weight. The mother sees it as maybe PCOS as well. Talks a doctor into GLP for the kid. Sometime not long later, the daughter takes her insulin pump off and is only injecting one unit of basal insulin a day, which goes on for a long time now. A couple of years later, her insulin need is rising again, just. Put her pump back on recently, etc. If all that on its face is true, what? What the hell happened? Why would a kid who's been using insulin full force for four years suddenly not need hardly a fraction of it for two years on a on, just on osempic?
Dr Steve Gittleman 50:20
Yeah. So this is a provocative area. It's extraordinary.
Scott Benner 50:23
And I know it's Yeah, yeah. Most people I talk to, if it helps them, they get maybe a 15, 20% reduction in their insulin needs, right? And I'll make the argument that maybe they have insulin resistance on top of type one, and that's why it's helping them. But this one specific story freaks me out.
Dr Steve Gittleman 50:39
Go ahead. I'm sorry, yeah, no, I think without knowing more details or studying this person more in a clinical research setting, it may be hard for us to really know. Let me see if I can set up the response. I went on and on about therapies to target the immune system. Part of our idealized therapy for type one is take the edge off the immune response and, you know, decrease that autoimmune attack. But what can we do to support the beta cell? What can we do to help it function better regenerate? We actually have lots of potential, promising drugs. On the immune side, it's still a big question mark on what to do to support the poor beta cell. Into that conversation comes the question about GLP, one receptor agonist, and a few other types of drugs these days in animal models, the study suggests that the GLP one receptor paragus might be doing some interesting things to beta cell survival, certainly function, maybe regeneration. There's been some hope that that could be part of the missing puzzle, and that if we combine immune therapy with this class of drugs. That's the secret sauce. The studies to date that I've seen haven't looked I mean, I think what they show is, if you have beta cell function, the GOP one receptor agonists are very helpful in in supporting the beta cell, in secreting the insulin it's capable of making it's not clear that it's altering the natural course of disease, that it's preserving beta cells longer or causing any regeneration. You know, in your particular example, I'm not sure I can fully answer the question. You know, it may be, as you mentioned, that it lowered insulin resistance, that there was pre existing beta cell function underneath everything, and it just helped the existing beta cells function better for a period of time, but ultimately, over time, the beta cells fade and disappear. When we talk about the honeymoon, it can be highly variable. And basically the number of those cells, the function of those cells, the durability of those cells, it's most closely related to your age of diagnosis. So two year old is who gets type one? I think that's what you mentioned your My daughter was just too Yeah, yeah. Yeah. She probably didn't start with very many, and they probably disappeared fairly quickly. You know, if you got type one tomorrow, you probably would have a lot more beta cells there, and they would last longer, and you'd have a much different experience for this child, adolescent that you're describing. Is so. What I should say is, at any age, despite what I just said, there's a great deal of heterogeneity. Some two year olds will have more of a honeymoon. Some adults may have a very short honeymoon, and some may have a very long honeymoon. So age is a proxy for something we don't fully understand in this process of beta cell destruction. But I think in your in your example there, I think the GLP one receptor agonist might have come in and helped support her underlying beta cell function. While it existed, she had a nice ride in her honeymoon. It just ended up fading, and then she's now having to give insulin back.
Scott Benner 54:21
Yeah, my expectation is that somewhere between the PCOS and the weight gain that was muting whatever kind of honeymoon she was going to have, and then you kind of lift that weight, and then the honeymoon kind of returned. It's almost how it like, I mean, that's a very rudimentary way of thinking about it, but like, that's the only thing that makes sense to me after talking to them a couple of times in the podcast and hearing their story, but I mean, she was literally down to injecting one unit of basal a day. Yeah, yeah,
Dr Steve Gittleman 54:51
that's quite a remarkable story. Yeah. And those, those are the kinds of stories. Those are like the breadcrumbs that we're talking about earlier. Is if we know unusual cases and try and tease apart how and why things are happening there, that might give us important insights to what we do moving forward with a, you know, a larger trial,
Scott Benner 55:13
no, I think so too is going to be quite a pivot. But you said that at some point you thought you were too bench focused and not paying enough attention to your to your patients, that's obviously happened a long time ago to you. Can you kind of lay out for me and for other endos who are listening, what your I guess, core theories are about how to support your patients. How do you, what did you do with that information you know, that experience, and how did you turn it into a practice that's been going for so long? How do you, what do you think the keys are to supporting people with type one in a clinical setting?
Dr Steve Gittleman 55:45
Yeah, that's a big question. A lot of this gets to the heart of just training and practice of clinical medicine in this day and age, I think traditionally, training is an in hospital experience. Most of what you know, trainees in medicine are learning is someone who's had an acute challenge and is admitted for ketoacidosis, and, you know, goes into the intensive care unit, out to the ward and then is sent home their next next intersection with someone with diabetes. You know, it's probably a very busy outpatient clinical setting where you know they may only have 15 minutes. How in the world can you really appreciate what life with a chronic condition like diabetes is about in those kinds of experiences? So I think part of the fundamental change for me, I just happened to maintain my curiosity about diabetes, despite the fact that I was working on a very reductionist aspect of Endocrinology in a laboratory. And, you know, I asked my department chair to go to diabetes camp one summer. You know that one week experience to me was just revelatory. You would think I would have known growing up my family and other types of experiences, but just kind of, you know, meeting kids, living with them, looking at how challenging it was to ask them or their families to make such complicated decisions, day in and day out. You know, there's no other condition quite like this, just trying to convey that challenge and making sure as healthcare providers that people have the empathy and realize the inadequacy of the tools that we're giving people. You know, I think that's a large part of what I tried to bring to our clinic and our team and just try and help people along the way. Yeah, that's lovely. That's part of what shook me up and just helped me shift direction. I will say one other fundamental change that I think has been great for pediatricians. You know, it used to be and you probably saw this with your daughter. Kids get up to graduate from high school, and you know this school says, Congratulations, here's your diploma on you go to college or your first job. We did the same thing in diabetes clinic. Yeah, you've graduated. We've done all we can for you. Good luck. And there's a lot that gets lost in those ensuing years as a young adult. And so one thing that has been very helpful to us with, you know, some of the change in healthcare legislation, and being able to follow people up to 25 now in a pediatric practice, through Obamacare and other mechanisms. You know, we get to support people through those further years. And so I think the baton is passed from healthcare provider to that young adult in a very different way. Now we kind of just ensure that all that success in the pediatric years is maintained as they move on to an adult diabetes practice
Scott Benner 58:59
carried over into a time when they can actually, you know, what do they talk about? You know, your brain is not fully formed till you're in your mid 20s, right? Like until it That's right. It makes a ton of sense to me. The, you know, I go back to over and over again interviews I've done with adults who are, you know, in their late 20s or early 30s, who retrospectively look back on their college years or after high school years as times when their parents said, oh, you know, you know what you're doing, and then they went off and they just completely ignored it for four years, or, you know, like or to put very little effort into their management. And then, as adults with a fully formed brain and an understanding of what had happened to them over the last decade. Come on here and tell me, I wish my parents would have stayed involved longer, even if I was pushing them away as an adult. Now, I wish they would have pushed back on that because of what I think I lost in my health by by allowing an ill formed person who's not ready yet. Take care of something so complicated to be the sole provider of the of their own care for those formative years right in there, yeah. I've just heard it so many times that I believe in it so strongly. Yeah, yeah.
Dr Steve Gittleman 1:00:15
One, one slide that I often use in educating, you know, trainees, and also with parents, is this image of a child riding a bike and then the parent, kind of running along beside them or near them to catch them if they happen to fall. So we really stress this idea that you're you're focusing on this, this, this notion of interdependence that you know maybe you're not hovering quite as closely I just would not fully let go. It's too important an issue. It's so much to ask in an adolescent and young adult who's got so many other things they're working on, staying involved and supporting as best you can through those years is super important to their long term success.
Scott Benner 1:00:59
It's an incredible balance to strike, and I'm in the middle of this with my daughter right now, between her spreading her wings and feeling confident and me not smothering her and also not allowing her a 1c to go from where we were able to keep it as a child to where it ends up for most people when they're 21 in college. So you know we are. The balance we're trying to strike right now is that she manages herself the way she likes, as long as her a, 1c, stays in the sixes somewhere, and if it starts to drift up too high, then we have another conversation about, hey, you need to Pre-Bolus. You know, when you see a rising blood sugar, we can't ignore that. You're gonna have to readdress it my daughter, you know, for transparency, we, I don't know if you call it micro dosing, because she doesn't do it every day, but she uses a less than therapeutic amount of of Manja No, which really helps, which really helps her, but be even down to, like, take your thyroid meds like you think that's easy. It's a little tiny pill. It's not that easy. When you're 21 to do it every day, you know, and to remember, I always say Steve, like, when this part's over, if she doesn't hate us and she's healthy, we won that. I give up and I'm done then, then I'm out that I'm that I'm sending a card that says, Congratulations on the birth of your diabetes. Good luck taking care of it. I gotta go. I can't thank you enough for for the time and the thought that you put into this. I'm going to tell you right now, while we're still recording, anytime you want to come back on for any topic that you think would be important for people to hear about, I'd be thrilled to have you.
Dr Steve Gittleman 1:02:32
Oh, I appreciate that, Scott, yeah, thanks for the thoughtful conversation. You know, I appreciate your questions and comments very much, a work in progress, but I hope we're leaving the conversation. You know, just hopeful we are getting there. I think the things that we're asking people to do with their diabetes today is going to get outmoded and get simpler and more definitive. Thank your family and all those others out there who are working through this. For your patients, it's taking time, but we are indeed getting there.
Scott Benner 1:03:06
I appreciate that very much. Okay, hold on one second for me.
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