0:01 Hello and welcome to an episode of Diabetes Dialogue, Technology, Therapeutics, and Real World Perspectives where we are live at the ACE 2026 meeting in Las Vegas, Nevada. My name is Diana Issacs. I am with my co-host Natalie Bellini and we have a very special guest, Dr. Linda Demaglio, who was honored with the Ellen Garber Award and gave a plenary keynote. And so we're so excited to have you as a guest and we'd love if you don't mind just introducing yourself and describing a little bit about your role and what you what you do. >> Sure. Uh so thank you for having me uh and uh for uh this is my first ACE meeting so it's been really great to experience it. I am a professor of pediatrics at Indiana University School
0:47 of Medicine. I've been there um almost 30 years. I currently serve as the division chief there. Um and I also run a type 1 diabetes research team um at IU. uh the team is focused on preventing type 1, a new therapeutics in the uh beta cell preservation space and then technology and therapeutics for people with established type 1 diabetes. Um I also work as vice chair of type 1 diabetes trial net and I'm co-chairing a study of neurocognition in young kids which I'm very excited about with living with diabetes and then I also uh run I'm co-PI of a national physician scientist training program. So a lot of different a lot of different hats. in that diabetes space. Yeah, >> that's really awesome. So, you gave an incredible keynote today. It was so well attended um and it heard rave reviews on
1:34 it. Um can you give us like a little bit of an overview of what you talked about? >> Sure. So, um I spoke about uh broadly early stage type 1 diabetes. Uh so I start off by talking about uh kind of definitions of early stage diabetes and who is at risk of diabetes which I define as people who either have known genetics that would predispose in the type one or um people have a single auto antibbody and then through uh stage one stage two stage three of type 1 diabetes. We talked about I talked about the screening landscape uh so where things are going in the increases in general population screening as well as the continued screening of relatives. We talked about approaches to monitoring, leaned on the uh breakthrough T1D consensus guidance statement in that
2:19 space which is a great resource and then talked about uh where we are with uh uh the uh therapeutics uh so tomom for early stage diabetes. I was excited to be able to say that it was approved uh yesterday uh uh down to the age of one uh for yeah stage two. That was that's a great advance. And then I talked a little bit about kind of where we're going in a lot of the open clinical trials, particularly in the stage three space, but also for stage two and stage 1 diabetes. And really the goal being that we want to try to end insulin dependence for people living with type one. >> Wow. I Yeah, I was really taken the number of different medications that people are thinking about using. I you know, okay, there's a handful. We all kind of know this, but no, there's a lot
3:06 of them. Yeah. So I I love that and and you know it's easy to identify someone as stage three. They're as a pediatrician most of them in your hospital today, right? So those are easy and you can then use a drug is it >> and the idea of can we do this quickly to preserve that residual beta cell function right now today. >> Correct. >> I that that was surprising to me. But I also love the idea that you said wait a minute why couldn't we go back to stage one? Why can't we give drugs in stage one? Why are we waiting to dismia? I love that idea too. >> Yeah. And some people would even say that stage one is late uh because you already have the autoimmunity. So what if you could even do things to prevent you know that beginning of the process and really go back because we know that the people's paths to developing type 1 diabetes vary. Uh so the reason that one
3:52 person develops type one and the second person may be very different but if we could intercede like as early as possible it would be it would be great overall. >> We're getting there. We're getting there. I think it feels like the the momentum in the past >> 5 to 10 years has completely shifted. Is that just me as a as a clinician from the outside because I do adults. >> Is it Can you talk a little bit about that? >> No, I think so. I mean, I think there's still that underlying frustration that we haven't found a cure, but I think that the reframing of cures was really important. Um, so that uh came from Aaron Kowalsski, I think at one point. I mean, people were talking about it, but I think he really messaged that out um through Breakthrough T1D. So, the fact that we needed to try multiple approaches. Um uh somebody asked me
4:37 recently like what the most exciting thing I was doing my research was and I firstly asked if I had to choose kind of one thing but uh overall I think that the idea that we're starting to use things in combinations is really really important and we really have intentional combinations. Um the trial that we just finished recruiting for in trial not using rettoximab followed by abbotasup was based upon a failed trial with abbotasup but data suggesting that epotasup would actually um be beneficial in people who had been treated with retoximab like the effects on immune cells look like that. I think that's exciting and I'm also excited about the idea of potentially personalizing what we're doing again based upon the ideology of diabetes in the person but also um other characteristics and learning more about how we can you know tailor treatment because you would never
5:23 at least for most cancers you would never just give one therapy for a few weeks and then stop and then say okay you're like you're cured. Um and with diabetes we keep trying to do those sorts of things and not like coming back in. So the other thing I didn't have a chance to talk about today which is like we also need to develop more intermediate endpoints so that we can rather than two-year ceptide which is what we tend to use to try to uh move that field forward. But I do think the energy I mean having a drug approved for stage two um has really I mean I have my masters in public health and so you don't want to screen for disease unless you have a treatment. So that helped us with that. So though we were pushing saying we can screen to prevent DKA, I think also have prevent DK but then also have a treatment was very important. >> I think so too. And I think your point of it took us so long to recruit for
6:11 right. It took us so long to get you know to get people to even be willing to screen the first time. Yeah, I do feel like that is that there is now a wave of people saying we really do need to screen and recognizing it because getting the first dipob trial executed took years and years and years to get enough positives to do the trial. Correct. I think this is that same idea. I'm feeling more and more people are requesting screening. >> Right. I think the other thing that we're doing a better job on which um is critical is really incorporating the voices and the perspectives of the people that we're asking to recruit into the trials. So, Trial Net uh finally set up a community advisory board I like uh which is expertly run by Christine March and Ingred Lman that Pittsburgh they'd
6:57 be great people to talk about on your podcast at some point but uh uh talk with but they um but just and so they're informing like the trial design of future trials uh the the community members and I think that'll help us figure it out um and uh figure out ways to get trials done more expeditiously. Yeah, you could give a whole like a whole separate talk like I I had to focus in my talk today on screening monitoring and then briefly talk about directions, but there's there's a lot in lot to think about in that space. >> Yeah, there's been a lot of talk on like eyelet cell transplants and I'm curious like where the research is going there. Are we going to see more success with that? >> I think it's very exciting. I occasionally people will ask me to like speak about that and I'll be like that is not >> my gig, right? >> It's not my gig. follow it. And I think somebody asked me today like when do you
7:43 think you'll have encapsulated eyelet cells that we can really I don't know. I I used to think of it as a race, but I actually think that they're kind of complimentary approaches. Um uh and uh yeah, I think that that that's that's also very exciting. I think anything that would uh reduce the daytoday burden and hassles that and they say that what people who live with type 1 diabetes make hundreds of decisions a day that people without diabetes don't need to make about everything food insulin you exercise you what are you going to do like even just like I mean coming to a meeting like this it was a hassle for me to get here and I don't live with type one but I didn't have to pack my my pods and my insulin and my you like all those different things um so if you could reduce the burden um whether it's through eyelet transplant or through having more beta cells through immune modulation. And I also think it's
8:29 possible that what we're doing in diabetes also will inform other disease states as well. I mean we were the first with diploma was the first disease modifying therapy for an autoimmune disease. So you maybe we can before onset right to delay onset. I mean we we took drugs that from psoriasis from um alopecia from um you know all all RA like all those kinds of things and we moved them back. But then you know can we also shift the paradigms for other other autoimmune diseases is I think the very interesting >> I mean what potential right like that's it's exciting that it's going that it has the potential to spread to to not just diabetes right >> it's a paradigm shift though for us I think in the field because I mean most of us who are endocrinologists firstly didn't well didn't go into endocrinology
9:14 because we wanted all this data that we have all the time around all the technologies and everything that we do in clinical care but also I I mean I didn't go into endocrinology ology to be able to you know uh to manage cytoine release and these immune modulations and infections and all that kind of stuff. So I love learning new things. So it's been interesting. Um and we've had to partner with people in other fields who do that much more routinely. But uh um I think it's I think it'll it'll change the these sorts of things will also change a little bit the the makeup of our workforce which I think is really going to be interesting as well. >> Right. You talked a lot about screening today and I know in the Q&A there were a lot of questions about like GAD auto antibodies. Can you talk a little bit about like how that isn't the most specific and kind of >> what do we do if it's positive or what
10:02 like why it could be falsely positive or >> Yeah, we had a lot of questions today about like what specific auto antibodies mean, what specific titers mean, the change in definition from the ADA to say that you don't need in stage 1 diabetes, you can have stage one or stage two if you're only single auto antibbody positive and how that moved the label uh for tlisma because the tipma label is based upon ADA stem. terms of care which is really also a really interesting paradigm. Um and uh uh yeah I think uh I think it's going to make for a lot more um thought I think around uh what which antibodies are the most specific and sensitive. Um for sure one of the things I kept saying during the talk to things I want anyone listening to this and anyone uh anyone uh who heard my talk
10:48 today to remember is that a single test riotlet auto antibodies is not enough. you need to if it's positive, you need to repeat it ideally in a different lab, ideally in a gold standard lab. For me, that my go-to is always the trial net. Um because anybody on the outside who is um antibbody positive can come into trial net and get all four antibodies, sometimes five antibodies depending the antibody profile tested um uh in a gold standard lab. And um but uh yeah, that low-level GAD was something people talked a lot about because it's not very specific to type one and yet you see it in somebody with diabetes and you're like is this type one or type two. One of the things that came out is the higher the tighter the more specific that could be and also the certain certain types of antibodies are more specific. Um although I think we are
11:33 sometimes seeing very even very high levels of zinc antibodies that don't don't replicate or may not repeat in another lab. But uh I think it's a nuance field. I think we need more data. We also need more data from populations that are not all like northern European um uh to figure out what this looks like in that and we need more data in adults um um from screening and also more data in adults with for drugs like diplomat as well. >> Yeah. Because in adults it's often the only auto antibodies check for and if someone has diabetes and then they're positive we assume they have type one but it kind of makes me wonder are we >> maybe falsely assuming sometimes I don't know. And in general um the in general I would for sure follow up in that case with all four. I think that will help. Um now something on insulin the insulin
12:19 antibbody won't be reliable. Um but uh and somebody with long-standing diabetes the other thing we talked about is uh >> you will sometimes lose those auto antibodies over time although often people will still have them. But uh yeah I think I think antibod it's nice that we can now code for it. We can deal for early stage diabetes. It's made that part a little easier. Um but a lot of the other thing that came up a lot in the discussion is how does what we're coding for and billing for effect insurance and willingness to reimburse for drugs as well. Um that's very context dependent. So in Indiana my experience with that may be different than than you guys would have in Ohio um or anywhere else in the country. But um yeah, there's there's there's a lot of nuance to what we do. I guess we're not we don't we don't we're not going to put ourselves out of jobs anytime soon.
13:04 Although we want to make our decision-m easier and be able to explain it to people in a more uh easy to understand way. >> Yeah, I think that's a big part of it. This one single antibbody this and and sometimes they dance, right? I mean, I've had I have a patient right now through trial net who was two antibbody positive for years, then she went down to one. Now she's at zero and she's the mom of a child with type one. So now we still have to continue to follow her because we kind of know they're probably going to go back maybe one day, but she was positive for at least two >> and not always the same two for several years right? >> It's really interesting. >> These are dancies, right? They're like, "Okay, I'm this, I'm that." >> And so that's the challenge with this too is it's not like it's a yes or no. It's not an on or off for everyone. And those nuances, I think,
13:51 >> people are people who would screen, they want a yes or no, right? And and clinicians want a yes or no. So they don't want to hear that you have to screen at, you know, 2 to 3, 4 to 6, 9 to 11. They want to say, is it on or is it off? >> Families want that, too. >> Families want that. I would want that, right? So that whole discussion is going to be something that as we have as we understand more about which antibodies, all of that, I think it's going to help us frame our discussions better, >> right? And make them easier to have. And as more of us have these conversations, it makes it easier to have. >> Yeah. >> Yeah. We're learning every day, I guess. >> Yeah. I'll say the other nuance I just want to answer quickly is that the the other thing that I talked about briefly and we're still it's like tanalyzing to me is that the antibodies may also vary
14:36 by time of day. Yes. >> And so when you repeat that, I I don't really quite understand why they do. It's been observed in other cases. We know that vaccines given at certain times of day are more or less effective. So it makes sense. You know, immune cells circulate by time of day. I mean, they're still going to be effective, but you can increase the efficacy of some things by giving it certain times a day. And so, I people people are asking me like, "What's the right time of day?" I'm like, "I don't know." Like, based on we've seen so far, people with established diabetes may be in the morning, but it varies based on the antibbody you're chasing as well. Um, but uh I think that's also something we need to continue to look at and understand in the space. Yeah, that is fascinating. >> It was I I that Yeah, that was one of those I'd never seen that before. >> Yeah. Yeah. You talked in the beginning about genetic risk. How come we can't do or we don't do more genetics for you? >> Well, people would advocate for that. I think it's uh my understanding is it's
15:23 been a little bit harder to scale that, but that's like not my my area of expertise per se. We have, you know, we do we tend to do um it may be somewhat reluctance to do genetic screening um uh in just a societal reluctance to do it as well. But uh there are certainly uh Bill Higgopian in particular is would be an advocate to say that you should do the genetic screen enrich your population and then do the screening. I think the other challenge there though is if you don't screen everybody if you say from a public health perspective you say I'm not going to if I'm only going to cap if I'm going to capture people based upon genetic risk score and then I'm going to follow them over time then you have to have a way to capture that population and really go back to them. Whereas if you're just going to have everybody like some school-based systems like they have in Australia, everybody
16:09 in that grade gets screened and they just come through in some ways even though you're screening more people. If you're doing it with a cheaper test and you're doing it to everybody, it may be easier than honing in on people early on. But uh there I I I think right right now I think where things are moving are to more multipplexed antibodies more than like widespread genetic screening, but we'll see. I could be wrong. Awesome. >> Wow. So much more to talk about. So many we need to have you come back next year and give us an update is what we need, right? Absolutely. >> So hopefully we'll have more data by then. >> That's exactly this has been a great discussion. We thank you so much for joining us and congratulations. >> Oh, thank you. Yeah, it's a huge honor. Um I learned a lot about Alan Garber.
16:55 His wife was here today. It was it was it was interesting. Um and um I feel humbled uh to be getting the award but excited to talk about this area of work. >> Yeah, you're very deserving. So we thank you so much for being here. We thank you all for tuning in and that wraps up this episode of Diabetes Dialogue, Technology, Therapeutics, and Real World Perspectives. Thanks everyone.
