Is Type 1 Diabetes a Slow Virus Disease?

00:00:00: Diabetes insights, breakthroughs and innovators.

00:00:04: The EASD TV podcast

00:00:07: from the

00:00:07: annual meeting of the European Association for the Study of Diabetes.

00:00:12: Hello again!

00:00:14: Now

00:00:14: viruses have long been implicated as a trigger of type one diabetes but it's a messy story And although enteroviruses are being fingered There are many other viruses too that have at one time or another been in the frame as a potential trigger for type I. To take us further into the story of infection and type I, can i introduce three people who were very well attended session?

00:00:43: Nutt Dahl Jorgensen from Denmark.

00:00:48: Oh, I'm so sorry.

00:00:50: Nutt Dahl Jorgensen from Oslo in Norway.

00:00:53: how could i have done that to you?

00:00:56: Then we have Haike Hoiti who's our virologist from Finland and Desir Eiseric for many places but currently Belgium via Brazil.

00:01:07: Yes

00:01:09: Who wants to start on this, perhaps as the diabetologist amongst our group here?

00:01:14: We'll start with you Knut.

00:01:16: What have been the theories so far and where are we in this constantly evolving story?

00:01:22: First of all I would like to say it's very important that we follow these track of defining if the virus is triggering type one diabetes because it may lead another strategy for prevention as we will talk about here also.

00:01:40: And that would perhaps be a cheap and simple path for preventing type one diabetes, so therefore it's important to follow this track.

00:01:53: It has been difficult to find the viruses but with new techniques as far as perhaps you'll tell us... ...it is possible now to detect very small amounts of viruses in the tissues And in Oslo, we performed a trial where we collected pancreatic tissue... ...in live newly diagnosed adult type I diabetes patients.

00:02:18: We detected the antiviruses in all cases and only ten percent of controls.

00:02:26: So that was strong argument for the virus to be important.

00:02:32: Then we performed phase two randomized trials using antivirals against the enteroviruses and we could detect an important effect that it would in some way preserve insulin production.

00:02:52: So, if there is a case where we can find the virus or an effect of antiviral treatment I think these are really strong arguments for viruses to trigger diseases.

00:03:05: Okay let's go our virologist.

00:03:08: There are lots of viruses, incredibly common in childhood.

00:03:12: I mean to be a child is to be infected with viruses and just because you find virus doesn't necessarily means it's the cause.

00:03:23: So where we're on that part of detective story?

00:03:29: Yes this is very important question.

00:03:31: so they...I think their last ten years have been very important in these kind of questions And that means new technologies have come in.

00:03:42: So now we can screen all possible viruses from human beings by sequencing, let's say stool samples with modern sequencing technologies.

00:03:53: so it means that we find all the viruses of the sample and what we've been doing for example is following children from birth And then when you follow thousands or ten thousand children, many of them develop diabetes during the follow-up.

00:04:12: Then we can go back to samples that were collected in the follow up and using these modern technologies detect all human viruses from their children.

00:04:23: For example a large study which did this very thorough examination found out were the main candidate among all other viruses.

00:04:36: There was also another virus group, adenoviruses which gave a signal.

00:04:41: but that's it.

00:04:42: so there are no other viruses... But can

00:04:45: I rest and thinking about enteroviruses?

00:04:48: There're lots of enterovireses.

00:04:50: Yes!

00:04:50: That is also true.

00:04:51: And then you have to ask questions like Among these more than one hundred enterovires types Are they some viruses, which are important in diabetes.

00:05:03: And that has been also addressed by the sequencing studies and antibody studies.

00:05:08: The answer seems to be there's a subgroup of enteroviruses called coxacchi B viruses... ...which really want to infect insulin-producing beta cells.

00:05:20: So they particularly

00:05:23: like pancreas?

00:05:24: Yes!

00:05:24: They want to go there.

00:05:26: There is a mechanism which is called receptor binding.

00:05:30: So the virus always needs to bind a receptor on the cell surface, so that it can infect cells and the beta-cells really express strongly these receptors.

00:05:40: with coxacchi B-group virus use And also in this big cohort studies like TELIS study or Finnish DIP study The coxakki B group has been among all enterovirus types Which showed the association of diabetes.

00:06:00: For example, here today we report our still unpopulist findings that when you sequence the virus from the pancreas disease what for example Knud has collected also those viruses seem to be these coxacipicrop viruses which you find in the pancreates of diabetic patients.

00:06:20: So Deciu there aren't as far I know although maybe some are production any vaccines against COX-ACP virus.

00:06:29: Is that the way forward?

00:06:32: I believe so, but this is something that CoIT is developing.

00:06:36: So perhaps you can explain how are you pursuing

00:06:39: it?

00:06:41: Yeah maybe i could take this question But there's a vaccine under development now.

00:06:49: It has been in phase one trial And targeting.

00:06:54: these COX ACP viruses have linked to diabetes and we know that it works in principle, so its immunogenic and safe according the first human trial.

00:07:06: And now it's progressing through next steps.

00:07:09: We hope that vaccine is needed to find out whether this virus really can cause diabetes.

00:07:17: because if we vaccinate part of the... In a randomized trial parts of individuals then others get placebo.

00:07:27: I hope so, that the incidence of diabetes is lower in the vaccinated group.

00:07:33: That's what we aim at prevention with the vaccine.

00:07:37: So

00:07:38: do you see it as a universal vaccine?

00:07:40: As part of their childhood schedules or perhaps from beginning offering to siblings and families who were affected by type one, although of course that would only pick up ten percent.

00:07:56: Yes if we can show the virus prevents diabetes I think then probably first it's going to be used in the risk groups like family members of diabetics or than if you do genetic screening for example at birth.

00:08:16: So polygenic risk scoring?

00:08:17: Yeah

00:08:18: but i think countries where you have a high incidence of diabetes, like Finland has the highest incidence in the world.

00:08:27: You see why do you... Why are you just full-of-coxacchi B viruses?

00:08:32: They're all over the place!

00:08:33: No it's the genes is genetic.

00:08:35: Oh so It's the genetics susceptibility plus

00:08:39: the virus.

00:08:40: I think nobody knows but ii think that's their answer.

00:08:43: its both and um.

00:08:45: Its very long story to explain how My bias is that the protection against these viruses is lower in Finnish children because the maternal antibodies which mother gives to their babies, newborn babies are at a lower level than most other countries.

00:09:05: So the Finnish newborns aren't very well protected against this virus and... That's what we have found in our epidemiological studies.

00:09:15: So the

00:09:15: scientists and all of us keep saying, why?

00:09:17: Why?

00:09:19: One thing that is interesting—and this is an angle that we are taking–is when the virus infects the eyelids... The beta cells evolve to a not-inune response… And they kill it!

00:09:32: And alpha cells that are neighbor cells survive.

00:09:37: so even long term type I, the alpha cells are there.

00:09:42: So the questions we are trying to answer is why the alpha cells in a way immune to the virus, while the beta-cells eventually die.

00:09:52: We have been comparing their gene expression and went a step further asking which other species completely or very much resistant to viruses?

00:10:04: And we focus on bats because bats can have rabies another virus and they don't develop any symptoms.

00:10:13: So we compared the global gene expression in bats against beta- and alpha cells, And alpha cells are closer to bats... ...and we identified one gene that is probably responsible at least in part for the Alpha cell protection.

00:10:34: so there it needs to learn from alpha cells and bats how to protect the beta cells.

00:10:40: So

00:10:40: could you develop something with an mRNA vaccine?

00:10:44: Yes, that's...

00:10:46: Do you have a colony of bats in Belgium?

00:10:48: No!

00:10:48: What

00:10:49: is happening today?

00:10:50: You don't need it.

00:10:51: we collaborative people in Israel That they have colonies of bats.

00:10:57: and but what happened today Is that people sequence all genes that bat different tissues express under baseline or following a viral infection.

00:11:09: And that is deposited online, so we just reanalyze the data with our round bioinformatics tools and compare it with alpha and beta cells.

00:11:21: So as long you have collaborators who have colonies of bats You don't need to have the bats at your garden.

00:11:31: It's a really fascinating story.

00:11:33: But there have been so many twists and turns in this particular saga, haven't they?

00:11:39: I

00:11:39: think if you look at all the firsts... Look at our white hair!

00:11:43: You get an idea how long it takes…

00:11:45: Because it must be fifty years since people said –

00:11:50: There was case that got lot of attention in nineteen seventy-one when published that the young child died of a ketoacidosis, and in newly diagnosed type I diabetes.

00:12:04: And by autopsy they could find the virus in the pancreas... ...and that virus was inoculated in mice who got diabetes.

00:12:12: So this case started about twenty years ago.

00:12:19: then it was possible to take pancreatic biopsies.

00:12:26: There were techniques for that, surgical techniques.

00:12:30: That combined with the possibility of sensitive essays coming up about virus detection then we could start these studies.

00:12:41: Yes I mean shotgun sequencing is something that's made it possible isn't really?

00:12:45: And maybe also as we talked about genetic vulnerability to have this persistence viruses.

00:12:56: Usually the most people they clear it, but some vulnerable that do not and then the virus site in the pancreas make functional problems And then induce the autoimmunity to kill cells.

00:13:13: So its not just infection But its persistent infection.

00:13:17: That's right.

00:13:20: There are also other examples.

00:13:23: In multiple sclerosis, they have found in epidemiological studies a connection between Epstein-Barr virus who will give mononucleosis and the appearance of multiple scelosis.

00:13:41: And we know that the Epstein–Barr viruses make persistent infections.

00:13:45: so I think that's in parallel is very interesting thing!

00:13:50: We also detected this virus in the thyroid of autoimmune thyroid disease.

00:13:56: And so it may be sort-of a general principle or disease, you know to immunity that viruses are important for triggering this?

00:14:07: I could perhaps add and i think the current state of art is not like most people acknowledge there's an association between enteroviruses type one diabetes And it has came from the big studies, big clinical studies.

00:14:26: Prospective studies as I mentioned to follow up from birth and those studies have been prospective.

00:14:32: so that means they had much better power to find these associations than previous studies in the nineteen seventies where first findings kind of came out.

00:14:42: then other important new angle or evidence is that people have in large international concertia found this virus from the pancreas tissue of diabetics more frequently than in controls using RNA technologies, protein technology targeted and non-targeted.

00:15:05: And then I think third important advantage What you are doing is the cell models and trying to understand mechanisms that why beta cells are susceptible for the virus.

00:15:20: And all these together, I think has sort of opened now a new era where this really seems to go forward.

00:15:29: That's why I think trials with antiviral drugs and vaccine are very important because they're needed to prove causality.

00:15:39: It's always difficult in medical science.

00:15:42: Yes, so you need to develop the vaccine because if you give the vaccine and then... ...you don't have diabetes… …then actually it really was the CoxAQV that caused it?

00:15:55: Very strong arguments for causal relationship.

00:15:59: In your view perhaps too early but in your estimation which percentage of cases would be viral related?

00:16:09: Yeah, that's also an important question.

00:16:12: We have estimated this with the calculations and we ended up to about half of T-one day could be linked into the enteroviruses but it is really artificial calculation.

00:16:25: so I think we need a vaccine trials to know what purpose... Yes!

00:16:31: And then if you had vaccines some other people who discovered did have enterovirus but didn't respond to the vaccine.

00:16:39: Is it because the vaccine wasn't working or because their T-one D was caused by something else?

00:16:45: Well, I think that's something else!

00:16:49: When you've got a virologist... You just need pin them into the ground don't

00:16:52: you?!

00:16:53: As i said we found an effect of antiviral treatment in newly diagnosed type one diabetes That they could in some extent preserve the endogenous insulin production which is very good thing.

00:17:08: And if we take this further and try to do, We would like that a new trial in those who have just the first stage with their appearance of one auto antibody.

00:17:21: If you give them the antivirals at that point maybe they can have an endpoint.

00:17:27: say if antibodies disappear the child is healthy.

00:17:32: So

00:17:32: that would be a very good trial to do because then we could be quite sure it was an anti-viral

00:17:39: effect.".

00:17:40: And this takes us back, I mean not... This was subject of your session but we've had lots other big sessions here at ASD about big screening programs.

00:17:52: Because unless you have screening programmes To pick up people who are high risk It's it would be difficult and you'd have to do a universal vaccine schedule And that would also be difficult.

00:18:04: So if all these things are interlinked,

00:18:08: yes

00:18:09: I think so.

00:18:09: we are leaving this transition from research to novel therapies an intervention.

00:18:17: one thing to keep in mind this estimation of fifty percent is that beta cells in the immune system, they have ways to sense the viral infection.

00:18:28: We call it danger signals.

00:18:31: so they have receptors for dangerous signals and probably most common are virus coxacia virus.

00:18:38: but there other dangers like even fragments DNA or RNA.

00:18:47: If the person has a genetic susceptibility and these receptors for danger signals, which we all have they will overreact when confronted with a virus or other dangerous signals.

00:19:04: It's fascinating area.

00:19:06: there is so much still to learn it one of those classic areas in science where you close one door, then a hundred and forty-nine other doors open for different investigations.

00:19:18: Thank you so much for coming in.

00:19:20: it's been a pleasure!

00:19:21: And of course if you want to see that session which sounds absolutely fascinating... ...then of course is available online through the EASD website.

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