Great. Hi everyone and welcome to today's hands on tips to improve diabetes care webinar. Today we have our panel, sharing with us their expertise on current insights in screening and prevention of T1D. We're very glad you're here. My name is Dr. Hiba Ismail and I'm a pediatric endocrinologist here at Indiana University. I'm also a physician scientist. I'll be moderating your session today. I'm also here on behalf of the diabetes in youth interest group, where I'm currently the chair elect. So for today's agenda, a couple of announcements. So we'll spend the next hour together by following the agenda on the screen. We'll be using the interactive features today. So we'll be using the chat box for links and information. And then we'll be using the zoom Q&A if you have questions for the panel. We also will be using a new interactive feature or tool called Kahoot during our webinar to ask you knowledge based questions and collect your answers in real time. So to talk a little bit about connecting to Kahoot, if you have a mobile phone or tablet nearby, that's often the easiest and best method to use. You can also use whatever device you're using right now, you'll just need to open a new window on your browser. To connect, open your browser and type Kahoot.it. Then enter today's game pin, which can be found in the zoom chat and on the screen. So I'll give you guys a few seconds. And the pin is 524-5410 in the chat box. All right, so another announcement, upcoming hands on webinars. So we have the next hands on webinar is on April 9 overcoming glycemic barriers through exercise and lifestyle. You can register for that. The link should be in the chat box. There is also the innovations and latest treatments in type 1 diabetes, which is an online self paced program, and you should have the link to register for that. There's also another webinar coming up actually sooner on March 19, appellant to GDF 15 understanding exercise derived signaling molecules in modulating metabolic health. You can register for that from the link in the zoom in the chat box. And then also please consider the innovation challenge and applying for that by March 15. So now I'd like to move to our panel and introduce our speakers. So we have first Dr. Jason Gaglia is an endocrinologist and researcher at Joplin Diabetes Center in Boston. He has interest in the development of better biomarkers for the study of type 1 diabetes or T1D and response to therapy. He is an investigator on the trial net study of teplizumab and relatives at risk for type 1 diabetes, which is the key study in the approval of teplizumab for delay and progression at stage two to stage three T1D. We also have Dr. Laura Jacobson, who's a pediatric endocrinologist and physician scientist at the University of Florida. Her research focuses on understanding the natural history of T1D, screening those at risk for T1D, and conducting clinical trials to delay and preserve beta cell function. She also studies the role and application of precision directed therapies, including immune therapies in the management of T1D. So I'll let our panelists take over and present their disclosures to you. Hi, I'm Jason Gaglia and these are my disclosures. Hi, I'm Laura Jacobson and these are my disclosures. Great, so thanks for the invitation today. So today I will be discussing a little bit about autoantibodies and their use in screening for type 1 diabetes. So the learning objectives for my part of the program are to identify those who are most likely to benefit from screening for pre-symptomatic type 1 diabetes, understand and describe the stages of type 1 diabetes, and understand the basis of interpreting type 1 diabetes-related autoantibody results. So I'm going to start from the ADA standards of care, and the relevant section here is within section 2, and relevant guidance is 2.6 and 2.7. And basically it's that screening for pre-symptomatic type 1 diabetes may be done by detection of autoantibodies to insulin, DAD, IA2, or zinc transporter rate, and that having multiple confirmed islet autoantibodies is a risk factor for clinical diabetes. And then testing for dysglycemia may be used to further forecast near-term risk, and when multiple islet antibodies are identified, referral to a specialized center for further evaluation and or consideration of a clinical trial or approved therapy to potentially delay development of clinical diabetes should be considered. So what's the take-home for this? So for me, this is that in areas where population-based screening isn't yet the norm, that we should really be screening family members, because that's basically the familial genetic risk score, and we should focus on those individuals for now by looking at these autoantibodies and then following up by dysglycemia testing as needed. So to follow up on that a little bit, you know, family history really tells us a lot about somebody's risk of developing type 1 diabetes. So risk of developing type 1 diabetes in the general population is about 0.3%, 0.4%, but if you have a parent, that becomes much more elevated. And interestingly enough, that risk is more elevated if that parent is your father versus if it's a mother. If you have two affected parents, the risk actually approaches 30%. In monozygotic twins, the 10-year risk is about 30%, but if you follow them out over lifetime, that risk becomes about 65%. But the vast majority of people have no known family history of type 1 diabetes, on the order of 90%, and that's just because the genes are very common, in particular HLA, and within HLA, in particular DR3 and DR4. So in 2015, we redefined what it meant to have diabetes. Classically, we thought about having diabetes as one presented with clinical signs and symptoms. So the description of wasting away a flesh into the urine, so the polyuria, polydipsia. But now we understand type 1 diabetes is an autoimmune disease, and it starts much earlier than the metabolic consequences that we see in hyperglycemia. So there's a fair number of the population that have genetic risk, and in particular, again, that's those HLA genes. And then in some of those individuals, immune activation occurs, and we're not really sure what those triggers are, likely environmental, because otherwise those monozygotic twins would be 100% concordant, and they are not. And it could be different for different people. And the beta cells are attacked, and in some people, the regulatory cells are able to go ahead and compensate for this, and the autoimmunity is shut off. And so some people might develop one autoantibody and then go back to zero, and will never go on to develop clinical disease. But other people go on to develop two autoantibodies. And once you develop two autoantibodies, at least if you're a child, at some point in your life, you'll likely develop clinical disease. And so this developing two autoantibodies, we now call stage 1 disease, which if you handle glucose normally in an oral glucose tolerance test, has a five-year risk of 44% developing clinical disease, and a 10-year risk of 70% developing clinical disease. If on that oral glucose tolerance test, you then develop dysglycemia, that two-year risk is now 60%, and five-year risk is now 75%, developing stage 3 disease, which is frank dysglycemia, and we refer to people who have longer-duration diabetes as having stage 4 disease. And so this is the data, and it doesn't matter if you're in Finland, Colorado, or Germany. If you follow someone from the development of autoantibodies, as you can see here, over a 20-year period, virtually every one of them will develop clinical disease. And so this is why now we say you develop disease, or stage 1 disease, when you first have these autoantibodies. Again, it's a marker of the autoimmunity, not necessarily the metabolic consequences. And so this is now the staging that is included in the ADA standards of care. To drill down on this a little bit further, you can see the definition of dysglycemia here for stage 2, looking at fastening plasma glucose, two-hour plasma glucose, and an oral glucose tolerance test, or even hemoglobin A1c. The other thing to note is that typically, autoantibodies are listed as multiple here, but they do not have to be by the time you progress to stage 2. As we'll discuss, you could have reversion of autoantibodies. Again, it's just a marker, it's the smoke, but if you've already developed dysglycemia, you've still hit stage 2 at that point. And we'll discuss a little bit about continuous glucose monitoring. You'll notice it is not currently on this table, as oral glucose tolerance testing-based metrics are still considered superior. But whether or not to perform an oral glucose tolerance test really depends on a number of factors, such as burden to the individual, whether or not the individual is looking to enroll in a clinical trial or have treatment, or even burden to the healthcare system. You know, are oral glucose tolerance tests available where this individual is? So here is looking at age of seroconversion to first autoantibody and progression of disease. And in the upper panels, you'll see people who develop insulin first. Insulin tends to be a first autoantibody in younger individuals, and the younger of these individuals seem to have faster progression, as opposed to, in the lower panel, we have GAD, where age seems to play less of a role here, generally because people with GAD developed it later, but you can still see progression for seroconversion of multiple autoantibodies. And so the message on this take-home slide really is, is the younger you are at age of seroconversion, the faster you are to progress to multiple autoantibodies, and in the setting of insulin being your first autoantibody, to the development of clinical disease. And so that was in the Finland DIP study. Here is from the TEDI study, and we see a similar pattern, that the younger you are at age of first appearing autoantibody is statistically significant, as well as the rate of progression to the second autoantibody, and then interestingly enough, the development of autoantibody against IA2A as your second antibody, as opposed to insulin or GAD. And so you're seeing here that when we're interpreting the antibodies, it's what antibody you develop first, what antibody you develop second, and age at which you develop this antibody. In this particular study, there was a female association with faster progression as well. And here is some summary data, again, looking at Finland, Colorado, and Germany, pulling this data together, and you can see here the number of autoantibodies is very important, and that if you have one antibody, your risk is, you know, less than 20%, and this is why we don't define one antibody as having even stage one disease. Once you go to two antibodies, that risk significantly increases, and three antibodies, it increases even more. With the caveat that we heard about in the TEDI study, that if you had a antibody against IA2, it carries a higher risk, and even with only a single antibody, as you can see here, that risk went from 20% to 40% if that single antibody is IA2. And if that IA2 is your second antibody, as you can see in the upper right panel, that increases your risk than if it was not. So IA2, as you saw in the TEDI study, and on this slide here, carries higher risk under the second antibody or as the first antibody. So when does this all begin? So you can see on the left panel some data out of the Baby Diab study, and you can see the peak in developing autoantibodies in boys and girls actually happens around age two. And so this is a disease that the autoimmunity starts very early, and it can happen years before the development of clinical disease. And as I alluded to earlier, just because someone seroconverts and develops a positive autoantibody, it doesn't mean that that's always going to be that way. So as you can see in the right panel, here's a child who is in the TEDI study and eventually went on to develop clinical disease, and you can see that the GAD antibody actually became negative over time. Yet this person still would be considered as having preclinical disease before they develop clinical disease, and this still carries important risk. So let's talk about that risk a little bit. So you can see here that if an individual in the right panel loses GAD, IA2, or zinc transporter 8, it really doesn't affect their disease course to developing clinical disease. And so there's bouncing around in those antibodies, you know, that person had it, it still counts. As opposed to antibodies against insulin, there actually is a little bit of a statistically significant difference. So if you lose insulin, which again tends to be an earlier antibody, younger individuals, that's a little bit of a good prognostic factor. But as you can see, the majority of people actually still go on to develop clinical disease. So what does this mean? Let's start putting this all together. And so one analogy that I've heard that really helps me think about this is the stages of diabetes are actually like the road markers. They're how far you are from developing clinical disease, but they say nothing about the rate. And so you could be walking, you could be riding a bike, you could be in a car, you could have very different rates as far as getting to the disease. And you really need to know both how far you are from the disease and how fast you're going to really do a good short-term risk prediction. And to me, this is the easiest way to think about it. So again, stage one, you know, you have a 30 to 50% risk of developing clinical type one diabetes within five to six years. So why such a broad range? Because you're in stage one, so you're very far away. And so rate plays a much more important role as opposed to the short-term risk. And so rate plays a much more important role as opposed to stage two, you know, you're at about a 75% risk at five years, and it's because you're much closer to stage three. And so your rate plays less of a role in this because you're physically so much closer when you think about it. So just to review a few nuances and autoantibody interpretation that we've discussed. So when you're thinking about this and you're thinking about the patient in front of you, you want to make sure that autoantibody conversion is associated with more rapid progression, particularly if it occurred at age less than three years, greater number of diabetes-related autoantibodies, development of autoantibodies against islet antigen 2, some additional caveats with this, and this is all included in the standards of care as well. Presence of autoantibodies should be confirmed. You want to make sure it's not just a fluke, particularly if you might have another thing going on. Because as you saw, the peak was around age two, but there were people on that graph who developed them at age five or age seven or age 10. So if you only screen at age two, you could miss them who develop it later. Unfortunately, we currently don't have guidance on the frequency and timing. Hopefully that'll be available soon. There is also different methods for measuring autoantibodies, and these methods do not always yield the same results. So if somebody comes from you from autoantibodies in one lab and you check it in another lab, it's not unusual for the results to be discrepant, and this is just where we are currently. And most of what is known to date is based on studies in children. There are studies going on, such as the T1DRA study in the United Kingdom, to try and get a better feel for what happens in adults. But right now, we are drawing conclusions from these studies that follow children. So the overall recommendation, moving into section three of the standards of care, is that in people with preclinical type 1 diabetes, to monitor for disease progression using A1c approximately every six months and 75 gram oral glucose tolerance test annually, but to modify the frequency of monitoring based on individual risk assessment, age, number and type of autoantibodies, and glycemic metrics. I'll be honest, this is really a bit of a placeholder in the standards of care, as better guidance is being developed, and it gives us a lot of leeway based on the factors that we've discussed to identify what is the appropriate testing and timing for a given individual. So why do we screen and monitor? So I think this slide is very important. Shown here in blue is people who were in screening studies with the T1DRA study. These were the usual setting of care versus those who received monitoring. And you can see the rate of diabetic ketoacidosis, which is listed over each of these bars. And generally, diabetic ketoacidosis, if you don't monitor, is about 20% to 30%, whereby if you are doing monitoring, you know, it generally goes down to about 4% or 5%. And so by monitoring individuals who are at risk, this significantly decreases presenting with diabetic ketoacidosis, which is important from a safety standpoint. Also, if you identify people who are in stage 3 diabetes with monitoring, you generally catch them with a much lower A1c. And so you're catching them earlier, and there is belief that due to metabolic memory, we're likely helping these individuals and potentially preserving beta cell mass by catching them at this earlier state. But since we are catching people by monitoring, a very important thing to keep in mind is just because you've diagnosed someone with type 1 diabetes based on monitoring doesn't mean they necessarily need to start insulin immediately. And so this is some data out of Columbia looking at the people there who were diagnosed as having stage 3 diabetes based on oral glucose tolerance test and or A1c performed at stage in the trial in that clinical study. And as you can see here, two-thirds of individuals, approximately, did not need to start insulin at time of diagnosis. And then if you follow them out, about a third of people, it was at one to three years that they finally needed to start insulin. And almost 10% of people didn't need insulin four years out. So again, it's a little bit of a different scenario diagnosing someone based on monitoring versus clinical presentation, which is what we're classically used to doing. So what can we do about it? You've identified somebody who has stage 1 or stage 2. You could enroll them in a clinical trial. Or there's other things that have been associated with slower rate of progression to stage 3 disease. And one of them is, so if you have less physical activity, you're more likely to progress faster. If you have higher dietary glycemic index, you're more likely to progress faster. And if you have greater total sugar intake, you're more likely to progress faster. Now, none of these have been associated with the development of autoantibodies. So again, these aren't associated with the autoimmunity. They're associated with the metabolic demand and what that might drive. We do not, however, have any clinical trials to date where they've tried to modify these risk factors. So all we can say is from epidemiologic data that these factors are associated with faster progression. We don't know if intervention will make a difference. So next in section 3 is there is now an approved drug. So for pharmacologic intervention to delay symptomatic type 1 diabetes, teplizumab infusion to delay the onset of symptomatic type 1 diabetes, stage 3 disease, should be considered in selected individuals age 8 or older with stage 2 type 1 diabetes. This is based on ADA criteria, as you saw earlier. And management should be in a specialized setting with appropriately trained personnel. And Laura will discuss this a little bit later on in her presentation. So the key take-home messages from my presentation are that type 1 diabetes is an autoimmune disease. And we now say type 1 diabetes starts when this autoimmunity is destined to have metabolic consequences. This is often long before hyperglycemia is identified. Measurements of diabetes-related autoantibodies can be highly predictive of development of clinical disease. Metabolic abnormalities define the progression or the stages of type 1 diabetes. Screening followed by monitoring decreases the risk of presenting with DKA. And intervention is now available to try and delay the progression of type 1 diabetes. So here's our first interactive quiz question. In autoantibody-positive children, which of the following have been associated with faster progression to stage 3 type 1 diabetes? Please click in cahoots on less physical activity, greater total sugar intake, higher dietary glycemic index, or all of the above. Great. So almost everyone got the answer correct, which is all of the above. I'm glad you've been listening. Thank you. Laura, over to you. Thank you, Jason. I'm very excited to be here with Jason and Hiba talking about this very important topic. And I think it's really cutting edge at this time because we all know that we can make a difference by screening and monitoring, but we don't yet know the best ways to do that. But we have ideas from research studies that all three of us have been involved in. So I'm gonna go over more of the metabolic side of monitoring for type 1 diabetes as Jason covered all of the antibody aspects. So my main objectives for this study are going to be talking about how even when you have autoantibodies and you're trying to identify if there is abnormal glucose tolerance, there is variability in who and how quickly someone will progress in those settings of multiple autoantibody positivity. So we'll look at different ways that you can monitor. Again, these are just kind of our and my thoughts on this right now. And there should be guidelines coming out soon that can help us all be very consistent in how we approach this. And then talking about our FDA approved therapy for delaying the onset in those who are at high risk for progressing to type 1 diabetes or how to refer people to clinical trials because that's gonna offer more therapeutic choices to individuals in the future. So this is just an overview slide that Jason and I have very consistent information that we wanna try and present to everybody. So screening for islet autoantibodies is a recommendation within the standards of care. If there's a suspicion or family history for type 1 diabetes, I included ICA here because clinically in some areas you can still get islet autoantibodies. And as Jason said, you may have two different assays provide different results, but if you're finding still multiple autoantibodies, that is still a high risk group even if those autoantibodies are not the same in both testing. And we're gonna go over a little bit more detail this differences in metabolic monitoring. So that's when we're talking about oral glucose tolerance tests, hemoglobin A1C, self-monitoring of blood glucose and CGM. We wanna identify these individuals because maybe we can delay when they might get type 1 because we can identify pretty accurately with some of these measures, over what time period someone may get disease. And then there are also clinical benefits to having a lower A1C and DKA reduction as we all know. So I'm just gonna briefly go over here some natural history that differentiates stage one from stage two. So when you just have autoantibodies without dysglycemia here on the left, this is a study that Jason's showed where you could have at five years, close to 40% risk. Whereas in trial nets looking at first degree relatives as opposed to individuals with genetic risk followed from birth, we can see once dysglycemia develops and that's just from an oral glucose tolerance test, your five year risk is approaching 80%. But is it 80% for everybody? So that's what I wanna go into a little bit. So why are we even talking about metabolic progression? Why do we care about catching this intermediate phase? So we know pathophysiologically, right? After you have infiltrate of those immune cells into the islets and around the beta cells, you not only have inflammation and signs of autoimmunity, but you also have stress on those beta cells. So they're not able to secrete insulin as effectively, but we know you can also see beta cell stress in type two diabetes. So back in the day when dysglycemia as a concept it was actually developed in the at-risk type two diabetes population. That group does not have the same insulin deficiency developing that you see in type one diabetes. So that is kind of the impetus for saying that's probably not the best measure, just dysglycemia for at-risk type one diabetes population. This is the same graphic that Jason showed earlier from the 2015 study, trying to really categorize these stages that do make it easier for us to discuss this time when type one diabetes is starting, but has not yet progressed to clinical symptoms. So again, I'm gonna focus just on this stage two area where you have multiple islet autoantibodies that are confirmed, and then you want to know what metabolic testing can be done and what does the results of those metabolic testing mean? I did want to show here briefly what the differences could be depending on where you're looking for your definition of dysglycemia. So we often think about a fasting glucose between 100 and 125, and then a two-hour glucose between 140 and 199 as being dysglycemic. We've done in our clinical trials that it got to Plizimab approved, and in the paper by Dick Insel and colleagues from 2015, that if you also look at the intermediate time points at 30, 60, and 90 minutes from an oral glucose tolerance test, and that has increased above 200 milligrams per deciliter for glucose, that can also be a sign of dysglycemia, even if the fasting and two-hour glucoses are not meeting that criteria. And then finally, what we can also see in the standards of care is very clear guidance on A1c. So having that A1c in that pre-diabetes range, but want to keep in mind, A1c, again, pre-diabetes range A1c was developed for pre-type 2 diabetes. So a single measure of A1c in this range may not be highly accurate, but studies are showing in our type 1 at-risk patients that a rise in A1c of greater than 10% may have more teeth to it than just having a pre-diabetes range A1c. So this is actually a graphic from a paper by Hibbe that's looking at oral glucose tolerance testing differences in the shape, or basically difference variability that participants may present with when they're doing an oral glucose tolerance test. So on the left here are the glucose values between zero all the way to 120 minutes for two different individuals that have different shapes to their oral, their glycemic response to A1c. Their glycemic response to the 75 gram glucose load. What we're not getting from when we use an oral glucose tolerance test for dysglycemia is what the C-peptide is doing at the same time. So C-peptide is easily measured at the same time during those time points and may also have differential responses to that glucose load that will add more specificity and accuracy to that prediction of risk of developing and rapidity of developing type 1 diabetes. So my future hope is that we use more of these what we call combination measures or risk scores that have been developed that include both glucose and C-peptide. But again, right now these are used in the research setting. I just want to introduce this topic knowing that dysglycemia is very familiar to everybody, but it may have some limitations and accuracy for type 1 diabetes risk. Just to give you guys a sense of what these measures may look like, I don't expect anyone to be familiar with these, but these three papers that I present here are just some of these complex risk scores that have been developed that include both glucose and C-peptide during an oral glucose tolerance test. And they're interesting because they use different time points. So if you're able to get only one time point, only one sample drawn from maybe a patient that's difficult IV access, you can still calculate a risk score that may provide more information than just using a single glucose value. So if we focus on the right-hand picture, this is called an M-score, which was developed using trial net data by John Wentworth out of Australia. And basically you could pick one of the time points here. I'm showing the 120 minute time point and the data that you can collect at that one time point can be aggregated into this equation. And if you have a elevated value for this M-value, then you have a much higher risk in your multiple autoantibody state than if you had a score below the median. Similarly, we see that with two other risk scores, one called Index 60 on the left and one called the DPTRS or Diabetes Prevention Trial Type 1 Risk Score. These were also developed from DPT1 and trial net data to say if we can include either over a full OGTT time points or just using kind of the first hour of an OGTT, and we can include BMI or age and glucose and C-peptide together, we can increase our accuracy of developing type 1 diabetes than just using a two-hour oral glucose tolerance test value between 140 and 199. So that's what these figures are showing. So they're showing survival curves by those who have more time that are diabetes-free shown in the first and third figure as blue lines. And then it's just inverted on the Y-axis in the center. This slide, I'm not going to spend much time on because Jason went over this very well. Why are we even talking about screening? Why do we want to add more work to the already stress time that we all have? And it's because we can really make a difference in reducing DKA, and DKA rates are only going up. So we need to be the ones that are advocating for this. And even though our patients may not be able to stay off insulin, if we're not able to get them therapies or in a clinical trial, just starting with a lower A1c and being more aware of that can have long-term beneficial effects. So reduce complications that are both acute and chronic. So I wanted to jump into kind of some practical tips or things to think about. And I think the most difficult group to think about is trying to identify first type 1 diabetes itself in adults and then adults who are at risk for type 1 diabetes, because they have a much milder, less aggressive presentation. So it's harder to identify, especially in the setting of obesity that's in, especially in the United States, we can get confused easily on what type of diabetes it is, but we know type 2 diabetes is so much more common that it really can make it difficult to pick out those individuals who have type 1. But I just wanted to remind everybody that more than 40% of the new diagnoses of type 1 diabetes are occurring in individuals who are over the age of 30, and we may be misdiagnosing that group. So now that we want to be identifying family members and relatives and other people for risk for type 1, maybe we should go back into our own patient panels and think about, this maybe hasn't been a classic case of type 2 diabetes. Maybe there are some of these red flags on the left-hand side here that I took from the standards of care from this year that may help us decide who we may want to do auto antibody testing in. And then that opens up a whole new population that can get appropriate treatment for type 1 and that their relatives can be screened to look for this risk. But if we just want to say now, who should I screen? How should I screen them? What can we do? Again, a lot of this is just my thoughts on this from working in research and doing these cohort studies, but kind of the lowest hanging fruit is still to screen people who have relatives with type 1 diabetes. They have a higher risk than people without relatives, but we do know we're missing a big population when we do that, but we're not doing a great job of getting all those people screened. So we can definitely start with them in our clinics because we have access to the patients and then we can reach out to their family member. Similarly, we may be seeing people in our clinic in pediatrics or adult who have pre-diabetes or our primary care cohorts providers. Pre-diabetes can still be type 1 or type 2 and we need to be thinking about does this fit the classic type 2 diabetes that runs through the entire family? Or are we seeing kind of a rapid progression in A1C despite consistent weight? So these are just things we should be thinking about for the people that we are physically seeing in our clinic, which are kind of a more captive audience for this type of screening. And then the antibodies I listed here, just to remind everybody, GAD, IA2A and zinc transporter 8 can be obtained at any time, but if you are on exogenous insulin, so say someone has been thought to have type 2 diabetes or during an illness was started on insulin and then came off of it, if they've been on insulin for longer than two weeks, then we don't wanna be getting that insulin autoantibody because we don't know if it's an antibody to the exogenous insulin or to the natural insulin that someone's producing. So what are some things that may get in the way of trying to do these screening tips in your general clinic? So it's hard when they're not your patient, right? So sometimes we can write orders for other patients that are not ours, especially if they've been seen in our healthcare system, but this might be a lot of asking our primary care colleagues for referrals to us or to ask them to do this initial screening and then we can help follow up the results because there's a lot of nuances, Jason said about which autoantibody is found, what age it's found. These are all things that are very complicated even for people within the field. So we really have to be here to support our primary care colleagues if they're gonna be ordering some of these labs for us on patients that are not our individual patients. There are lots of efforts within the community in type 1 diabetes to actually create billing codes for these early stages. So hopefully coming maybe later this year will be ways that hopefully we can get reimbursed for our time for seeing these at-risk patients, which will help kind of our superiors allow us time to care for this population. And then we are trying to develop some workflows as part of the type 1 diabetes exchange and other efforts to kind of help people have practical ways to implement these in a clinical setting. So hopefully more to come on that. But as I have on the bottom of the screen here, you can order autoantibodies from clinical labs like Quest and LabCorp. And I'm showing here at our institution that there is a panel for adults that includes four autoantibodies. And I even favorite them within Epic. So if I have a relative and I can go in real quick and just order these four antibodies and give them a lab slip, that my time can be kind of saved a little bit by already having those orders favorited in my Epic orders. But say someone doesn't have insurance or you're worried that their insurance may not cover this testing. Although usually if you have a family history of type 1 diabetes, that is a billable ICD code. But there are ways to get these labs done at no cost to the patient. So there are kind of two main efforts. One is through TrialNet, which we are all a part of. That is a across the country clinical trial consortium that screens first degree relatives between two and 45 years old and second degree relatives up to 18 or 21. And I have a website on the next slide that you can use to direct patients to that they can have a kit shipped to them and they can take it to a local lab like a Quest or a LabCorp. And then TrialNet will handle following up the results and reaching out to the families with the results of their antibody testing. And we'll also do the monitoring follow-up should autoantibodies be found on a confirmatory sample. The other is the ASK program out of Colorado. So this is the Autoimmunity Screening for Kids program that screens for type 1 antibodies and celiac antibodies. It actually also includes adults, but it's just been initially marketed to kids. And it's, you can request, families can request a kit and it's sent to them and it's through a capillary test. So through a finger stick and then the results go back to Denver. So here are two screenshots from the websites for TrialNet and for ASK that can be easily directed for patients to request their own screening kit at no cost. And then TrialNet, if we reach out to families, if they're eligible to let them know about any clinical trials that we're doing in the prevention space in stage one or stage two to help continue to find drugs that delay the onset of type 1. So a lot of people ask about general population screening. Should pediatricians, family medicine internists be going into their clinics and screening everyone? We do know there's a benefit to screening. We know there's a benefit to monitoring. It is my personal opinion that we're not quite ready to be in the general population yet. We want it to be reimbursed. We want to have clear and consistent guidelines and not conflicting information. And we are very close. And gen population screening is being piloted in several places. And actually in other countries like Italy, it's being instituted as a nationwide program. And in Germany, they've been doing this very effectively as part of pediatric primary care visits. We in the United States are getting there, but I do not want to overwhelm our colleagues or ourselves with trying to handle a big influx of results, because there are a lot of barriers and things we may be creating for ourselves that I'll go over on a future slide. So this is a great paper by Kimber Simmons out of the Barbara Davis Center in Colorado, where it gives some initial guidance on what to do when you've screened for autoantibodies and you have a result back. And this is not something that you are normally involved in research, and you're not sure what the next step should be. So if you screen negative, it is important to know, are there still risks? Does someone still have an autoimmune or a type one family history, especially if they're a child, probably want to consider screening them again in a couple of years if they're still in the pediatric age range, because they may still develop autoantibodies. But if you screen negative for autoantibodies as an adult, the risk is very, very low that you will develop autoantibodies later. It's not negative, but just the yield is much lower. Well, what if you get antibodies that are positive? Well, mostly we want to look at those multiple, if you get two autoantibodies positive, but like Jason said, sometimes a single IA2A may have a higher risk than just having multiple autoantibodies. So we want to say, well, what's something quick and easy that they recommended in this paper that could help you identify, is there an acute metabolic risk? Does someone already have type one diabetes and they just haven't had kind of frank symptoms to bring them to healthcare yet? So an A1C and a random glucose can help with that. And obviously if your A1C or random glucose are in the diagnostic range, then they are being sent to an endocrinologist or to the emergency room if we're worried about DKA, and we can kind of get that ball rolling and we've caught it. We've still caught it early, right? They're not coming in vomiting with abdominal pain. If they have kind of a glucose that's in this dysglycemic range or an A1C in the prediabetes range, those are people that we as endocrinologists can follow. And that's what these, there are monitoring guidelines from the JDRF coming out soon that can help give us clear guidance on the best ways to do that. But what we want to do first is let's say, let's really confirm if these antibodies are there. This is not a perfect lab test, as Jason talked about. So we want to actually repeat the antibodies. It can be in a different lab or the same lab, but we want a separate blood sample to say, you know, is this truly there? Is this not a false positive? And if we get two autoantibodies or more again, that is a group of people we need to follow. And then I am going to show on this next slide potentially different ways that you could follow people. But there will be a lovely paper coming out very soon by the JDRF working with all different organizations, with ADA, with ISFAD, a bunch of groups to come together on a consensus for monitoring for metabolic dysfunction. But the different ways include self-monitoring of blood glucose. So teach them how to do a finger stick at home and have them do it at different intervals, right? This is not something that someone needs to be checking their blood sugar every day. These are not people with diabetes, clinical diabetes yet. So, you know, maybe they could do some fasting and some two-hour after their largest meal. But again, we don't have clear guidance yet on how frequently. Also, we've known this for a while. If you're sick, you know, if you're going through an illness, you may have some more hyperglycemia then. That may be when type 1 diabetes presents. So that could be a time to check glucoses. Hemoglobin A1Cs, again, are something we can do very easily in clinic. But I think following A1Cs over time and seeing what the change is, is more valuable than looking at a single measure. And then there are different depths of testing you can do using oral glucose tolerance tests, which is still, as Jason said, the standard of care that gives us the best measure, especially if you include C-peptide at the same time you're getting glucoses. And then CGM is, there are studies that are trying to identify the best cutoffs and time for identifying risk of progression with CGM, and it's coming along. It's coming along. So not to overwhelm anybody, but this is my opinion about what I would do with the different metabolic measures that I mentioned and cutoffs. Again, these are just things that in research we've learned can identify a high risk group of people and if I identified someone with a rising A1C or elevated index 60 or an M120, again, these are not things you need to be doing, but these are things I know increase the likelihood of progressing to clinical type one. That is a group of people that I will now follow much more closely. If I was maybe, you know, seeing them once a year, every six months, I may say, let's just touch base in three months and let's see how you're doing. Because you may be approaching the stage, especially if you do an oral glucose tolerance test or have a prediabetes A1C, where you may meet the criteria to get T-zealed if you have stage two type one diabetes and are over the eight years or older. So if you're eligible for that therapy, and that is something that the family is interested in, we want to know that information. So I had a couple cases here that I just wanted to kind of let us think about to help think of different ways we can monitor people. Again, there is no one right way. These are just different things that people can do, like Jason said, when you have different access to different technologies. So the first case on the left is if you have a three-year-old patient who is the sibling of a patient you see with type one and their three-year-old sitting in the corner of that visit, and the mom says, oh, yeah, I'd love to get them screened. That would be great. Since you have them in clinic, maybe you just like do a quick A1C and glucose finger stick. And then you find out that their A1C is kind of borderline. It's not as low as you would expect, but they've got a normal random glucose. So in that situation, something I would do is I would create a chart for that patient. I would have our office staff make a chart, because that is a relative of someone with type one. I would use that as their reason to see me. And then I would order the autoantibodies either through research or clinically, and that way we'd start that process following that child. Whereas if you have a seven-year-old I listed here, you know, maybe the pediatrician's very progressive, and they went ahead and ordered these autoantibodies. Even there's no family history. Great. They find two autoantibodies, and they even did the next step, which is they confirmed them. They got another blood sample, and there are two autoantibodies. They're just different autoantibodies. That still, that person meets stage one type one diabetes with multiple autoantibodies, and it would be good to find out this seven-year-old is at risk for their age of kind of being a faster progressor to clinical disease. And it would be nice to get a baseline A1C or a random glucose, as mentioned in Kimber Simmons' paper. And then maybe I would see them every, you know, six months and do an A1C. And if I start to see that rise, then maybe I would put a CGM on them as we kind of get more information. But I also refer them to trial net to see if there's any trials for their age, because they're too young to qualify for teplizumab if they meet stage two criteria. Next, young adult, 22 years old, has other autoimmune disease, finds out they have one autoantibody. So what we want to do is we want to see if that confirms. If it doesn't confirm, meaning there's no autoantibody on repeat testing and they're an adult, I probably would do no further testing for them besides monitoring what, like giving them advice on symptom, symptoms to watch for, for type 1 diabetes. And then finally, if you have a 40-year-old, you may say, oh, I'm not going to worry about them. This may be someone who's still at risk for type 1 diabetes. And even though they have some mild or mildly overweight, they have a family history of diabetes and they want to be tested. So you get autoantibodies if you're like, this is not really fitting the picture of my type 2 diabetes picture, pre-diabetes. So if any of those antibodies are positive, then, you know, an oral glucose tolerance test is easy in this age group to do. And then I think I, this is one of my last two slides, just focusing on, we talk about screening and all the reasons we want to do it. It's still very hard. It's hard for patients and it's hard for providers. So for patients, we want to make sure they're not getting charged for this. We want this to be something that is covered by insurance or done on a research basis still. We need to be reaching everybody with this. If we have something we think benefits a patient population and we are not reaching all races and ethnicities that are affected by that, because everyone is affected by type 1 diabetes, we need to change how we're doing things because we're not doing a great job in our clinical trials and research yet of being, of getting everyone who is eligible. And then we want to be doing this with the patient in mind, what are their goals? What are, what do they want to know? Because there's a lot of anxiety that comes from knowing you may be at risk for developing a disease or your child is at risk for developing a disease, and they may not want to know the answer to that. So we need to talk about that and have counseling available and potentially screening tests to look for this anxiety or distress. We don't want to be inducing any inappropriate behaviors because of screening that we're doing. Same thing from the provider side. We need to get this information out as we get more concise guidelines, but it's going to take provider time. We worry that we're not going to get reimbursed and how do we fit these people into a schedule that's already full because there's not enough of us. So these are all things we need to work out before we have a huge influx of patients. And then T-ZILD, I wanted to just go over the trial briefly. We know that from the individuals who were in the trial net study, they had a median of three years delay in the onset of type 1 compared to the placebo-treated group. We know that the criteria for the FDA approval is stage 2 type 1 diabetes, but it's not a super easy infusion to do. It's 14 days back-to-back, an IV infusion. It doesn't take very long, but you can have some nausea, fatigue, fevers, rash, things that can be tough to manage if you were not prepared for them and using pre-medications. So there are protocols that are shared between different groups, especially trial net centers. So you can always reach out to any of us individually by email and we can help share protocols. And also Sanofi has hopefully access to all of that as well if interested. And then, oops, this was my fault. The fonts did not match. But basically what I want to say is if you're trying to get T-ZILD for a patient that you have, that you can use their Compass website and they can help you find either a location that has been set up already or help you set up your site if you're interested. And you can see here all the places that patients have been infused. So these we've already gone over. So I'm just going to move now to our quiz question. So which patient is potentially eligible for T-ZILD using the current FDA-approved indication of Stage 2? 25-year-old, one antibody, impaired glucose tolerance. Seven-year-old, two antibodies, impaired fasting glucose. 15-year-old, two auto antibodies, impaired glucose tolerance. Or a 41-year-old with an A1c that is 6.7 with multiple auto antibodies. That's a lot to read quickly. But it is the 15-year-old here. And just very briefly, that's someone who has the right age and the right metabolic state. This 25-year-old at the top only had one antibody. The seven-year-old is too young for T-ZILD. And this 41-year-old, you could be concerned they already have clinical Stage 3 diabetes. So with that, I will leave this up on the screen and let Hibah take over. Thank you. Yeah. Thank you, Laura. And thank you, Jason. So just a reminder, here's the five key tips and takeaways. We'll leave that up here. I'm not going to go through them all, but it's a quick read. It should be a quick read. Oops, I lost it. All right. So I'd like to thank our panel for their wonderful presentation today. If you haven't already, please ask your questions in the Q&A. I know I saw a few pop up. And I know Jason responded to one of them. And then there was a question very quickly about, let me read that out, about intestinal alkaline phosphatase deficiency and risk of developing diabetes, whether it's Type 1 or Type 2. And this was a question posted by Dr. Malu. Dr. Malu very kindly put a lot of data up there for us to consider. So that's very interesting. But I don't know if Jason or Laura wanted to comment on that. I don't want to comment on that. I don't think this is really the talk for that topic. But I did want to comment, the response that I gave, I actually gave it privately. So I don't think everyone saw it. So I'm just going to read the question, because I think people would benefit from this question. The question was, does a parent with different autoimmune disease, such as rheumatoid arthritis, confer risk to a child as a parent with Type 1 diabetes? And so as I commented in the talk, the family history is the poor man's genetic test, basically. And so because you have a family history of one autoimmune disease, that does increase the risk. And with rheumatoid arthritis, there actually is a shared gene, PTPN22, which increases risk for both rheumatoid arthritis and Type 1 diabetes. So it is theoretically possible that having a family history of rheumatoid arthritis would increase your risk for Type 1 diabetes. That being said, if your family history is in Type 1 diabetes, that's probably, for most people, a stronger association, because generally the at-risk HLA for that particular autoimmune disease is then shown to be in the family as well. So it's not just the associated genes like PTPN22, but the HLA genes. And so I'd say both increase risk, but in most families, a family history of Type 1 diabetes would increase risk more than other autoimmune diseases. But any family history of autoimmune disease does increase risk of Type 1 diabetes. Thanks for the question. Really quickly, is there a recent reference that discusses different assays and their sensitivities? Either of you. Jason? Yeah. I mean, there is basically workshops that are done regularly that compare the different assays. There unfortunately hasn't been a workshop paper for the last few years, so they're not super recent up to date. I know several groups that are working on a comparison paper, including TrialNet. But Laura, do you know of any really recent publications? So no, that comparison paper that Jeff Krischer is doing in TrialNet, I think will be very, it's like the current assays. So Enable and different clinical labs. So that is not out yet, but that hopefully will be coming in this year sometime. I think that will be a great reference for all of us. Okay. And I see very quickly, you want to take a question, Laura. If an adult has low fasting C-peptide and postprandial glucose values in the diabetes range, normal BMI, negative antibodies, is this likely type 2 diabetes? Yeah, sorry. I wasn't sure what I was clicking either, but I just wanted to bring up that even though we have these great auto antibodies, it may still miss about 5% of people with type 1 diabetes. So if they otherwise look like type 1 diabetes and they need insulin within a relatively short period of time, it may still be type 1 diabetes, even though the antibodies are negative. But that's a case where maybe the antibodies could be repeated at a later time. And just to keep the clinical picture in mind, but those are tough. Okay. Thank you. So we'll have to wrap up very quickly, but I just wanted to remind people that this is being recorded. It'll post in a few weeks on the ADA's website, and you'll be getting an email to answer a survey so that you can claim CE credit. Thank you again, everyone, for attending and for the panel, for the presentations, and obviously the ADA staff who have supported us and coordinated all this work. Thank you. Have a good afternoon.

diabetes care

Type 1 diabetes

screening and prevention

autoantibody screening

metabolic abnormalities

A1C tests

oral glucose tolerance tests

teplizumab therapy

high-risk individuals

TrialNet screening kits