Type 1 Diabetes: A New Beginning

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00:00:06: Welcome back to EASD TV.

00:00:09: My name is Vivian Parry and I'm delighted to be your host, especially this morning because we have with us.

00:00:18: Annette Ziegler is the winner of this year's Claude Bernard lecture.

00:00:24: And that it, It's The Most prestigious award That the EASD offers.

00:00:30: So firstly Netta Congratulations!

00:00:33: Its a wonderful, wonderful recognition Of the work you've done.

00:00:38: Now You're primarily known for your work on prevention of type one diabetes.

00:00:46: Tell me how did the life of Netta Ziegler start?

00:00:50: What made you get into this area in the first place?

00:00:54: It started actually at a community hospital, is where I started medicine to work into medicine, and it was a department that's specialized in diabetes.

00:01:10: I got there by chance at the end of my studies at university but then i started to like uh...to work there.

00:01:19: But I didn't really have the intention to do science!I did not even start doing thesis But people kind of convinced me that it is also interesting to do some research.

00:01:32: And, uh... It was by chance.

00:01:35: I was involved in a first project about a trial with cyclosporine as one of the first immunotherapy trials in type I diabetes.

00:01:47: And this try was actually successful, improving insulin secretion and thereby somehow supporting the concept that Type I diabetes is an autoimmune disease.

00:02:01: From then on, I was in contact with international colleagues around immune-based therapies.

00:02:09: I thought it was so interesting that I got into the field.

00:02:15: It is extraordinary, isn't it?

00:02:17: Some younger people listening to this will be astonished at the start of your career when they did not know that Type One was an autoimmune disease.

00:02:27: Yeah, indeed.

00:02:29: It was only that time that eyelid antibodies were detected.

00:02:34: I mean they were detected a little bit earlier.

00:02:36: but then it's coming into the textbooks of medicine and still one couldn't distinguish so easily what is type-one in type two diabetes?

00:02:46: And also at this point called juvenile diabetes or adult diabetes.

00:02:54: It was called insulin treated and non-insulin treated, diabetes.

00:02:58: So it was not so much distinguished that there are two different pathogenesis about the disease?

00:03:05: It's extraordinary to think we didn't know that!

00:03:08: You begin to pursue this idea of immunotherapy but immunotherapy wasn't... The success now is what were problems you experienced then

00:03:20: At that time?

00:03:21: it was a treatment, but also had side effects.

00:03:24: And I think at the end of day one has decided... ...that benefit is not large enough to accept the risks of these kind of treatments and then already in those times when considered whether it's also enough to treat after type on diabetes has developed, or whether it would be better to treat even before to prevent that disease.

00:03:54: But at the time also we didn't really have tools to predict and diagnose who is developing diabetes in.

00:04:02: an earlier kind of milestone or breakthrough in my career was that I went to US, through the Choslin Clinic in Boston.

00:04:15: To a wonderful mentor George Eisenbad and where I learned about different markers to diagnose this disease early And we started to study family members not those who had already diabetes, but those who did not have diabetes to identify those at risk.

00:04:41: And this is I think where early detection somehow began... But there were still a lot of steps to do!

00:04:51: So at the time this idea that you needed to find people early was really important one.

00:04:59: because Well, certainly the public think that when you develop type one diabetes it's like a light switch.

00:05:08: It is on or off but in fact the pancreas still has functioning cells and the process started some years before.

00:05:19: so finding natural history must have been really important to you?

00:05:23: Yes actually at the time I was in Boston George Eisenbad had just published a more or less theoretical model, how type one diabetes could evolve.

00:05:37: How the pathogenesis would look like with a triggering advent and then the process is starting at going for years until beta cells are lost in clinical development.

00:05:52: And when I saw this model, I thought how could we really test these in humans?

00:05:58: When it begins.

00:06:00: This was one of my great ideas that came back to Germany... ...I started the first pioneer of birth cohorts where we followed at that time family members who already had children newborns from birth, who were the parents' hard type on that beat is to find out when do these eyelid antibodies first appear?

00:06:29: When does this whole process

00:06:30: start?".

00:06:32: I think it was a kickoff of several following-birth cohorts.

00:06:37: Of also the TETI study as an international birth cohort and we really learned an enormous amount from these natural history studies.

00:06:50: And the difficulty is of course, even with people first-degree relatives with type one.

00:06:59: actually there's still not that many of them because most cases are in people who don't have relatives with Type One.

00:07:08: so how big did your birth color heart to be?

00:07:10: To capture a very small number

00:07:13: We followed about one thousand six hundred babies from parents.

00:07:19: One of the parent had type-on diabetes, but then following birth cohorts already went a step further because they included people in general population who have increased genetic risk and that was very important as at this time we didn't know whether pathogenesis is similar between someone with a family history or does not have a family story.

00:07:44: And we could actually prove by the several of these studies that pathogenesis looks very similar across countries, across the world and across people with and without genetic risk.

00:07:58: So what

00:08:01: came next?

00:08:02: In this birth cohorts We asked several questions.

00:08:05: Question one was when it starts and big surprise that actually it started within the first two years of life.

00:08:17: This was very crucial later for what we have today, early detection because it told us when to screen

00:08:24: number one people believe before this

00:08:26: or he had no idea.

00:08:28: We thought more or less It can start any time in live still can.

00:08:33: but we didn't know there peak incidents in the first two years of life, that the maturity developed it already that early.

00:08:43: The only hint really in hindsight was there is a mouse model for type one diabetes.

00:08:51: all mice develop insulitis, inflammation and also antibodies already with four weeks of age.

00:08:58: So it is a little bit similar that there must be something early in life And we think now today It's the beta cell itself because actually some modeling going on more activity around the time That maybe makes it more vulnerable.

00:09:15: so this process starts earlier.

00:09:18: But to know this, that there is a good time-to-screen was actually very important.

00:09:26: Fascinating!

00:09:26: Also for the pathogenesis to know when to look for triggers and modifiers of environmental exposures of that disease.

00:09:37: Screening never an easy process.

00:09:41: so how did you start thinking about your screening journey?

00:09:46: Yeah, this was the second important question that we after... The question of when does it start?

00:09:52: We wanted to know if it started.

00:09:54: How does it evolve?

00:09:55: Does everybody really develop that disease?

00:09:58: and This is when we combined three birth cohorts studying over thirteen thousand children prospectively And we had already follow-up.

00:10:06: then over twenty years kind of every child who had at least two antibodies developed clinical disease.

00:10:16: And this was the origin, I say... ...of early detection.

00:10:20: that was the paradigm shift-the kick because now we know when this disease begins namely when two or more eyelid antibodies are detected and this is a tipping point for type one Diabetes.

00:10:37: and we know, We can screen an early detect this disease early.

00:10:41: And now that these people really develop the sees so bad was to start in when you had this finding after twenty years of birth cohorts.

00:10:52: then I actually started first public health screening early detection to integrate it into regular care, not regular care in public health research and try to find out the general population whether this is a feasible thing.

00:11:15: So at that time you were thinking of screening more so than I think soft landing could be provided for children who developed diabetes because they would have these episodes of diabetic ketoastosis which were incredibly scary and dangerous for everyone, parents the child.

00:11:39: And at that time I guess was your main focus wasn't it?

00:11:44: That you'd somehow be able to provide this soft landing and prevent these episodes from decaying.

00:11:51: Absolutely!

00:11:54: like me, I also worked all the time in a clinic with people with type one diabetes.

00:12:00: And with diabetes you see these severe cases happening and that is something very important even as specialists scared of this diabetic ketosis because it's really dangerous situation.

00:12:18: Yes we wanted to to prevent severe complications at diabetes onset, but of course also we had always somehow in mind already that there are clinical trials.

00:12:32: To prevent this disease and that would also really provide access to the general population to participate in these trials because you know before it was only first-degree relatives that had the chance to be treated and participate for disease modifying

00:12:50: treatments.

00:12:51: About thirty five percent of cases, isn't it?

00:12:53: Yes!

00:12:53: And also if you... I mean we all know that now have a treatment to slow down their disease, a monoclonal antibody to please them up.

00:13:03: but this drug was tested in Trianet only in First Degree Relatives at that time because there was no possibility for everybody to have the chance to participate.

00:13:15: So that's an extraordinary turnaround, isn't it?

00:13:17: Because in some ways... In your early days working with immunotherapy It hadn't gone anywhere.

00:13:24: You know, immunotherapy had been hyped at the time.

00:13:29: There were lots of talk about this But actually they haven't really delivered.

00:13:33: And yet here we are now With a treatment which does deliver.

00:13:38: Yes This is an enormous milestone for the field that we have one treatment, that can delay.

00:13:46: But I think there are many others now in the pipeline that are tested and very high likelihood And i'm confident within a short time it will have range of these therapies That can delay progression.

00:14:02: Of course It all depends on being able to screen babies effectively

00:14:07: Yes, or young people.

00:14:10: Now we have actually a consensus and an international consensus on when to screen also publication that just came out before this meeting here two weeks ago where we recommend screening at two to four years at six to eight years and then also between ten and fifteen years.

00:14:32: So, we recommended three times just have a very high sensitivity to detect all people that develop this disease.

00:14:43: And you see the screening ages are in childhood.

00:14:46: We haven't so much experience yet with adults But we believe that the majority of people who develop this disease, even in adulthood have these autoimmune antibodies already in childhood.

00:15:00: So will detect them by screening?

00:15:03: It also leads to another big question is what is the trigger?

00:15:10: because it seems and correct me if I've got this wrong but a genetic propensity plus a trigger and then the development of type one.

00:15:22: And has this work shown us any more information about triggers?

00:15:28: Yeah, no it's very important that you ask this... It is actually that we changed a little bit the word.

00:15:35: We started with trigger because maybe there was something like helicobacter

00:15:42: or something.

00:15:45: But now I think we believe rather that there are, how do you say?

00:15:51: I don't know what the saying is in English.

00:15:52: Several ways... several paths to this disease and i would more call it modifiers of the disease, modifiers for susceptibility And um..I think there's some strong evidence that infections are such a modifier of the disease, particularly in young children.

00:16:15: Because there is multiple evidence.

00:16:19: I think at least five studies that found an association even claims data on viral infections, respiratory infections in early life and also number of infections with increased risk to develop or start this disease.

00:16:38: So we are looking for these infections, and one of the infections that we have seen is even during the pandemic SARS-CoV-II to be one of these candidates.

00:16:51: And we're actually now testing this in a clinical trial where we give the COVID vaccine to children from the age of six months to protect them.

00:17:04: These are the critical ones, and this is a placebo-controlled trial where we at the same time collect saliva samples in babies to test fourteen other viruses.

00:17:19: And we collect these samples weekly... ...and it's very surprising how compliant those families really want together with us weather viruses and which of them really is associated with type one diabetes, so we have over fourteen thousand saliva samples already collected.

00:17:42: And be hoped that this will give us more insight into this kind of trigger?

00:17:49: It's fascinating isn't it?

00:17:50: because you have in the general public they all think there has been an increase.

00:18:02: Tanymi is that COVID vaccination actually protects children against type one.

00:18:09: Yeah, this is what we are testing and we need to see whether it's really turning into the case.

00:18:16: But let me talk about one other environmental factor.

00:18:22: It is actually very interesting because it's a protective fund, what we also found if a mother has type I diabetes.

00:18:29: the child only have half of the risk to develop this early autoimmunity than her father with Type I diabetes And we very much try now to understand the mechanism behind that, because it would be also a pathway maybe for therapy if you know what protects this child in early life from this first peak of insulin autoimmunity.

00:18:59: Some kind of uniparental disamy or something like that?

00:19:02: Yeah, we don't know.

00:19:03: I mean... We see for example that the epigenetics and methylation patterns are different in those children And they're different In type one immune genes.

00:19:15: So it could be that The activity of these genes also in terms of cytokine levels activation Levels for T cells Are different from those children.

00:19:28: That causes this protection around them.

00:19:32: So for you, type one has been a treasure chest from which you've taken out more

00:19:39: and more

00:19:40: shiny things that nobody knew were in there.

00:19:43: I mean it is completely astonishing to me.

00:19:45: when you started people had no idea that Type One was an autoimmune disease.

00:19:52: At the end of your career, I hope it's not at the end but towards that you had ever thought possible.

00:20:05: Of course one always has a vision and early in life somehow do something that this disease does not develop because I saw what it means for people to have type one diabetes.

00:20:20: And let's say the dream, but you don't know.

00:20:29: But I think still we have a lot to learn and a lot do.

00:20:34: As i said before, We need more treatment for people.

00:20:41: And also we must understand the rate of disease progression because it's quite variable.

00:20:50: you can progress within one year like having full natural course or take sometimes fifteen years And we have a lot of markers already to predict and distinguish, but I think this is to understand the difference in rates.

00:21:12: Maybe also something where you can learn which therapy to use when?

00:21:22: What do you contribute to your success?

00:21:27: I know that you've had an institution at the Halmholtz in Munich, which has always been incredibly supportive.

00:21:33: But what's helped you in this extraordinary journey that you have had?

00:21:38: Absolutely my team and This is what I wanted to say at the beginning.

00:21:44: It's a recognition of my work, but it has been a team effort absolutely and... ...I was very lucky to have a team that worked with me for many years.

00:21:55: so there are many people who stayed with me long time just working together having experience in your team.

00:22:08: we all really contribute work.

00:22:12: I think that was somehow very important and they even started with me in this community hospital, we came to Helmholtz together.

00:22:24: And

00:22:26: also it's one of the great joys doing what you do.

00:22:31: people living with type-one is seeing them from babies through adulthood.

00:22:40: All those people.

00:22:42: Yeah, also the families and you know in this first birth cohort they are now thirty six years.

00:22:48: They have their own babies And we were always thinking about having a transgenerational study where We look at that next generation.

00:22:58: but That was at the end too difficult to do.

00:23:00: But yes it is very nice.

00:23:04: It's been a wonderful career.

00:23:10: And Annetta Ziegler, thank you for telling us about your life with type one prevention.

00:23:17: It's been extraordinary!

00:23:20: Well, Annetta's Claude Bernard Lecture... You can of course see online and it is well worth listening to.

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