Corinn Cross, MD (Host): This is Pediatric Insights, advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Cori Cross. Today we'll discuss Type 1 diabetes auto-antibody screening and the importance of early detection. We are joined by Dr. Abha Choudhary, who is a Pediatric Endocrinologist at Children's Health and Associate Professor at UT Southwestern. As well as Dr. Soumya Adhikari, who is a Pediatric Endocrinologist at Children's Health and a Professor at UT Southwestern. Thank you both for joining us today.

Soumya Adhikari, MD: Thank you for having us.

Abha Choudhary, MD: Thank you.

Host: So, I'm very excited because today we'll discuss the importance of autobody screening for Type 1 diabetes and its potential for early detection. And early detection is so important in identifying at-risk individuals, and can really improve patient outcome, reduce complications and help guide timely interventions. So let's start with understanding Type 1 diabetes as a whole, as an autoimmune disease. Can you walk us through the pathophysiology of Type 1 diabetes, specifically, how the autoimmune destruction of pancreatic beta cells leads to the onset of the disease?

Soumya Adhikari, MD: Yeah, you're alluding to it already in just how that question was asked, which is that we all regulate blood sugar levels in our body, you know, 24/7 within a pretty tight range. And yet in a person who's developing Type 1 diabetes, the ability to keep your blood sugars in a tight range, which is typically maintained by the continual and episodic production of insulin, kind of goes awry because the cells in your body, which make insulin, make insulin in response to your blood sugar levels.

And those cells, which are the beta cells in your pancreas, fall off in number because your own immune system begins to mistakenly recognize your beta cells almost as if they are invaders to your own body. And as a result of that, your immune system attacks your pancreas and causes you to over time lose your beta cell population leading to your inability to make insulin in sufficient quantity to keep blood sugar levels in control. Unfortunately, we know a lot about the condition. We don't know everything. We don't know every single thing that triggers your immune system to turn against your own self. But we do know that the incidence and prevalence of Type 1 diabetes is unfortunately rising almost at a clip of about three to 4% a year across the world.

Which translates today to about one in 300 children in the US is living with Type 1 diabetes. Which if you think about that from practical terms, you know, there's probably at least one person with Type 1 diabetes in almost every school in the country.

Host: Yeah, that really does put it in perspective. So now that we've had some background, can we narrow on the specific autoantibodies and how they play a role in Type 1 diabetes progression? Specifically, could you explain how the presence of autoantibodies like GAD autoantibodies or IA-2 autoantibody help in predicting the risk of developing Type 1 diabetes?

Abha Choudhary, MD: Absolutely. I also would like to add that the risk in a first degree relative such as siblings or children of patients living with diabetes, is roughly 5% or one in 20. So family members are at 15 times greater risk of developing Type 1 diabetes, compared to the general population.

Host: So we have to assume that there's like a genetic risk factor there?

Abha Choudhary, MD: Correct, correct. So if there is an identical twin with diabetes, the odds of the other twin developing diabetes is about 50%. However, we know that 90% of those who develop Type 1 diabetes do not have a family history. Moving to your question, so there are no direct measurements of the immune process or the beta cell decline.

The clues to the immune targets in Type 1 diabetes is by detecting these auto antibodies that are reactive with the islet cell protein, in individuals with and prior to the diagnosis of clinical Type 1 diabetes. So these include auto antibodies to insulin, GAD65, Zinc Transporter and the protein tyrosine phosphate, which is the IA-2A.

So auto antibodies can identify the risk of progression to clinical Type 1 diabetes. And risk is modified by age; younger the age, higher the risk, and the number of auto antibodies present. So younger individuals frequently have the insulin auto antibodies and the GAD65 is frequently found in the teenage years.

IA-2A is associated with more advanced autoimmunity and faster progression to stage three. Now interestingly in an individual who has a positive family history, and a single auto antibody, the risk of progression to stage three or clinical diabetes over five years is only 6%. However, the risk of progression from one to multiple antibodies over five years is around 22%.

Now, if there are two or more positive antibodies, which is now defined as stage one diabetes, the risk of progression to stage three diabetes, which is the clinical diabetes, is 44% over five years and about 70% over 10 years, and the lifetime risk approaches a hundred percent. In addition, if the individual has abnormal glucose tolerance, now which is now referred to as stage two diabetes, the risk of progression to frank diabetes within five years goes up to 75%, and the lifetime risk approaches a hundred percent.

So once an individual is in stage one diabetes, progression to stage three becomes inevitable. And the risk is same with two or more autoantibodies, whether or not they have an affected family member.

Host: So are you saying that there's no one who develops these antibodies, who can then sort of, if you look at them in five years, would not have the same antibody profile? Meaning that they would have less instead of more? Does anybody go in that direction?

Abha Choudhary, MD: So the antibodies stay, their glucose profile may change. They may be dysglycemic or they may be normal glycemic. So stage one is when they have two or more positive autoantibodies, but they are normal glycemic, meaning they have normal blood sugars. Stage two is when they have two or more autoantibodies, but they have dysglycemia or they have abnormal blood sugars either measured via glucose or hemoglobin A1C or on an oral glucose tolerance test.

Host: Okay, but you did say that everybody who makes it to stage one eventually progresses to stage three.

Abha Choudhary, MD: That is correct. So this justifies the idea of intervening in such an individual, if possible, to delay the development of frank diabetes.

Host: That's exactly what I was going to ask you. So if we know that this isn't a false positive, it's just a prediction of what is going to happen, and the question is, when down the line is this going to happen, it makes sense for us as pediatricians or you as endocrinologists to do our very best to intervene so that it slows that progression and it changes the disease process. Correct?

Soumya Adhikari, MD: I think that's always been the vision, right? The work that's gone into our current understanding of the state of the science of Type 1 diabetes development has been going on for decades and part of the goal was always to be able to predict who is going to develop Type 1 diabetes. What do we understand about the importance of genetics? What do we understand about the importance of antibodies? But if that was all we ever accomplished, I think we would all feel a little dissatisfied with what did we accomplish. The vision has always been a larger one to, if we can predict who's going to develop it, can we do something to slow it down?

And the exciting part about where things stand today is, I think a lot of us in the field feel like we are beginning to scratch the surface of how do we actually modify that inevitability of Type 1 diabetes development. And that's just as big a reason for why we're trying to get a word out about the importance of screening and the importance of early detection.

The reality is that the benefits of early detection go beyond just delaying the onset of disease. I think the largest studies that have been done to date show that unfortunately, 30 40% of children who are diagnosed with Type 1 diabetes don't present to medical attention until they're pretty metabolically decompensated, meaning they're really sick.

They've been eating a lot for weeks. They've been drinking a lot for weeks, and it's gone unrecognized because until you see it, you don't see it. And it's not uncommon for children to be very sick. Or what we in the field refer to as being in diabetic ketoacidosis at the time that you present, which is a state of decompensation that unfortunately carries some pretty significant morbidity and at times mortality as well.

And early screening, the numbers seem to suggest can reduce the prevalence of DKA at the diagnosis of Type 1 diabetes from somewhere in the 30 to 40% range, all the way down to less than 10%. So it's all the benefits of can we delay the onset, can we make your landing into the onset more gentle? All of those things are behind why we're trying to get the word out about screening.

Host: So let's discuss screening a little bit. What are the practical challenges and barriers you see to implementing universal screening in pediatric practices?

Abha Choudhary, MD: The main barriers are healthcare provider knowledge and readiness in management of early stage Type 1 diabetes. So education and collaboration with the primary care physician, I think in my mind, is the key to success. The other barrier is of course, insurance coverage. You know, screening family members, if there's a positive family history, the reimbursement rate is pretty spotty. But, it's unclear if the payers will reimburse general population screening at this point. So it's not a part of the American Diabetes Association guidelines at this time.

Host: So logistically, if I were to draw these labs, can I send them to any lab or would there be specific labs that do a better job of detecting these antibodies?

Abha Choudhary, MD: So there are screening programs such as TrialNet and ASK, and these target relatives of people living with diabetes. TrialNet is a US-based consortium and ASK is autoimmunity screening for kids, which is based in Colorado. So ASK also screens kids for celiac disease. But these are the two big screening programs.

There are other genetic screening programs in the country as well, such as Cascade and Pledge, but they offer auto antibodies screening to those individuals who have a positive genetics risk score. So they combine genetic screening and offer autoantibody testing to the ones who have a high genetic risk score.

The screening can be done in any lab. It can be done in a Lab Corp, or Quest, or a local lab as well. So pediatricians can order screening on their kits. TrialNet is easy in the way that you can order a home kit, which can be delivered to your house and needs a spot of blood.

We at Children's, we have started a TrialNet screening clinic, which is free. And the families can call, and schedule an appointment for free screening in our clinic. So it's easy to screen.

Soumya Adhikari, MD: You asked about barriers. If I can just add one other thing to what Dr. Choudhary said. I think there's no clear one set of guidelines for who should be screened and when should they be screened and when should they be rescreened. There are developing guidelines, but I think from the pediatrician's perspective, there's still a need for a uniformly accepted set of screening guidelines, that are endorsed by major pediatric organizations that advocate for appropriate reimbursement for these efforts and that come along with educational efforts to help the general pediatric community in understanding how to have some of the at least initial conversations with families who are considering screening, so that they can be guided through that decision.

Do I want my children screened? What if they have relatives? What if those were distant relatives? What if it's a couple generations removed? There's a lot of questions that are still needing to be fleshed out a little bit to make it easy for the general pediatric community to offer screening in a wider scale.

Host: Yeah, and as a pediatrician, I am thinking, I'm understanding this correctly, if 90% of the kids who are going to have Type 1 diabetes don't have a family relative or a genetic component that we can see when we just take a family history; then if those are the only people we're screening is that 10%, we're missing a large percentage of the kids that are going to eventually develop Type 1 diabetes.

Soumya Adhikari, MD: For sure, and you can enhance that a little bit by saying, well, 90% don't have a history of Type 1 diabetes, but a broader percentage than 10% have a family history of some other autoimmunity. So even for you know, a pediatric practice that feels uncomfortable jumping in feet first all the way into, let's screen everybody; if we just begin to offer screening to children with a family history of any other autoimmune condition, we're beginning to make some inroads in terms of, well, what's the highest yield screening going to be?

Host: And if you did decide to screen everyone, at what age would you suggest doing it and how often?

Abha Choudhary, MD: So there are some suggested ages, as early as three to four. And then, if that is negative, the next timeframe is seven to eight years of age, and then around 13 to 14. So again, these are all suggested ideas, but there are no definite guidelines yet.

Host: And I think I know the answer to this, but I'd love to hear your opinion on it. How should healthcare providers approach the balance between basically potential anxiety on behalf of the families and the benefits of early detection?

Abha Choudhary, MD: So looking at the literature, the evidence shows that the parental anxiety is initially really high. But decreases over the first year of following screening. So assessment and management of anxiety, as a part of screening are required to adequately support families. So what I've noticed is pairing scary information with actionable items helps to decrease anxiety.

And ISPAD, our national Society has published best practice guidelines, for monitoring and management to help PCPs and endocrinologists to manage early stage diabetes. So following those guidelines, having actionable steps, hopefully will help to elevate anxiety.

Host: Dr. Choudhary do you have any resources you'd like to share with us for your local pediatricians?

Abha Choudhary, MD: We started our screening clinic at Children's in October, 2024, and we've been seeing individuals with positive antibodies referred by the primary care physicians. So if you have a patient, please refer them to us. We also have a teplizumab infusion center set up at Plano. We also offer clinical trials for disease modifying therapy for newly diagnosed individuals with stage three diabetes.

Host: Well, thank you both. This has been so educational. Is there a 60 second take home message that you'd like to leave our listeners with today?

Abha Choudhary, MD: So it is time for us to think about Type 1 diabetes differently. We now know that there are preclinical stages that we can identify with screening, and if found, we can intervene to change the course of Type 1 diabetes. Teplizumab is the first FDA modified disease modifying drug approved in stage two diabetes, which can delay the development of stage three diabetes by an average of two years.

Host: Well that's all great information. Thank you so much for your time with us today and to our audience for listening to Pediatric Insights, Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research.

You can find more information at children's.com. And if you found this podcast helpful, please rate, review and share it. Please follow Children's Health on your social channels.