Hello and welcome to equine Endocrinology. What's new? My name is Ruth Morgan.

I'm an equine endocrinologist, at the SRUC and the University of Edinburgh, up here in Scotland, and my specialty really is around glucocorticoids and stress hormones in. Obesity and PPID and EMS. So today I'm gonna build on an update I gave a couple of years ago for a webinar vet, which really covered quite a lot of the basics, and where we were up to that point with our understanding of endocrine diseases.

And today I'm really gonna focus on what's new. So, if you do want to go back to the previous, lecture I gave, I, I would, if you want some more of the background and some more discussion around, the, the understanding of pathogenesis, diagnosis and treatment of each of these diseases. Because today what I'm gonna do.

Is try and give you a summary of what's been out there in research over the past 2 or 3 years, I can't possibly cover everything, because there's been a lot, it's a very, vibrant area of research, but I, what I've tried to do is draw on things that I think are really important for you to take forward to your clients, . And for you to understand when you're interpreting tests or dealing with these clinical cases and introduce some of that ambiguity which we know surrounds these diseases and which can can make treating them and diagnosing them very challenging. So we're gonna cover what's new in the pathogenesis, diagnosis and treatment of both PPID, so pituitary part.

Media dysfunction and equine metabolic syndrome, EMS. And we're gonna start with a very quick recap of the pathophysiology of pituitary parts intomediate dysfunction, just because it feeds into a bit of what the new research is telling us. So the pituitary is the master gland.

It sits at the base of the the brain, . Quite inaccessible in the horse. And it consists in the horse of three different lobes.

And there's the anterior pituitary, which is the parts destylus and the pars into media lobes, and then the posterior pituitary. It's a source of all the main hormones, honestly, and, and they act to control all the other endocrine glands. And it controls most of the functions of the body, so it really is the epicentre.

But there are some differences in the course compared to other species, and, and that what that's what makes them quite unique in terms of this disease, pituitary part intermediate function, which seems species specific. So if we talk specifically about the anterior pituitary, that is, it is the main part of the pituitary which makes up the eight different, sorry, the 5 different cell types that you have there, producing all of your hormones that you will have heard of, so your reproductive hormones LH. And FSH and thyroid stimulating hormone and and growth hormone prolactin.

And then your posterior pituitary really covers your, anti-diuretic hormone and or vasopressin as it's called, and your oxytocin, and we'll talk about those in a second. We just look at the comparison between the horse pituitary and other Pituitries. You can see the horse pituitary is this nice kind of, almost, like a squished, a squished, shape.

And that's quite important when we talk a little bit about diagnosis with MRI later. It's slightly different from other species pituitries. And so in the middle here, you have the posterior pituitary and it's stained blue here because it's essentially projections of nerves straight into the pituitary from the hypothalamus.

In between, you have number 3, which is the intermediate pituitary or the pars intermediate, and then round the outside, you have the anterior pituitary, which is the source of all the other hormones. Now, you'll notice in the rat, you've got an intermediate pituitary there, labelled I, but in the human pituitary, you don't. You just have the parts nervosa or the posterior pituitary, and the parts.

Stylus, which is the anterior pituitary, and that's because the melanotropes, which make up the pars intermediary in the horse and in the rat, are actually supersumed into the anterior pituitary, during gestation. So the foetus, the human foetus has a pars intermedia, but, but as gestation goes along, those, those cells get. Taken up into the, into the past to stylus and become, just discrete pockets of cells, which is quite interesting.

So we go back to the hormones, just to very quickly recap, but the posterior pituitary hormones are your classic ADH or vasopressin and oxytocin. So ADH deals with your water balance. You might have come across horses with, nephrogenic or central diabetes incipidus, and that's usually due to a, a change in the release, or, or the detection of ADH, anti-diuretic hormone.

And then oxytocin is the classic milk letdown hormone and uterine contraction hormone and maternal bonding. So they're quite different and quite separate from our anterior pituitary hormones, which come from the past stylus and include all of these that I've just talked about, . So your reproductive hormones, your thyroid stimulating hormone, prolactin growth hormone, and of course, ACTH.

Now it's really important to note that the majority of ACTH comes from the anterior pituitary, and that's the same in the horse. So what's the pars intermediate? Well, the pars intermediate, unlike the anterior pituitary, is made up of just one cell type, and that's melanotropes.

But what they do is they produce a very large peptide called a pom C peptide, so proopiomelanocortico corticotropic peptide, which gets cleaved into different peptides depending on what the enzymes look like in the cells. And so this is the other source of ACTH cos the, the pom Cs get cleaved into a beta endorphin. Clip, which is corticotrophy like intermediate peptide, which has insulin regulating effects.

ACTH and alpha MSH. So mainly alpha MSH, but then also ACTH. So ACTH is not primarily come from the intermediate lobe.

It mainly comes from the anterior pituitary. That's important when we're we're remembering what it does. It's a stress hormone, it acts on the adrenals to cause cortisol release.

The main thing that comes from the pars intermediary is alpha MSH, but we don't often measure that. So that's important, and it brings in a bit of ambiguity in terms of what we're measuring and when. And we'll talk a bit about that, when we, when we go on to, to what's new in research.

So this is just to highlight what happens when you get a tumour or a hyperplasia of the pars intermedia. So on the left here is the plastic grading system created by Miller, 1 to 5, where you've got a normal pars intermedia at the top here. Between the pars anterior, the anterior pituitary and the pars nervosa, the posterior pituitary.

And then you get a gradual hypoplastic growth, and you can see that also echoed in the panel on the right, which are samples from my horses that I've been working with. And then you get true adenomatous growth. So there's definitely, a difference between a horse with hypoplastic PPID and ones.

With a full adenoma. But what we really don't know is whether it's a spectrum of one disease, or whether there are distinct subtypes. So will all horses, we know not all horses with PPID look the same, but the question is, do they progress, from one type to another?

And I think clinically or anecdotally, we don't necessarily see that. So there is quite a lot of work going on to distinguish whether there are actual subtypes or whether you could tell by any biomarkers that we might have, whether a horse has a hypoplastic parts intermedia, which might be more easily reversed, or whether it has a true adenoma with disruption of the mitotic cell division and, and a true tumorous phenotype. It makes a difference because maybe this .

Influences how the horses respond to treatment, maybe it influences the clinical spectrum that you see. So I just wanted to, to introduce that slight ambiguity of we don't really know if this is a spectrum, and when we're talking to owners about whether the disease will progress, we really don't know the answer, because obviously we, we'd have to euthanize the horse in order. To get the histology on the pituitary, and we would tend to euthanize them for other reasons potentially other than PPID.

So we don't know what their pituitary started off like, and, and then, and how it's got to where it's ended up. So it's a very difficult disease, to, to, to grasp in that sense. There's so much we don't know about it.

In terms of the pathogenesis, well, the, the long held belief is that, dopamine is the main inhibitory signal in the pars intermediate. So you get a consistent dopamine signal. It also, dopamine also inhibits, other signals to the pituitary and certainly in humans it does.

So you get these long dopaminergic, neurons which project from the hypothalamus, and they inhibit the pars intermediate, the melanotropes. Now the idea is that these neurons regress or they're lost in some way or damaged in some way, and that reduces the dopamine input. And if you take away inhibition, then the cells can start to replicate further and further and further and you can get tumorous growth.

And this has been the long held belief for a long time, and there's, there's definitely more evidence now that this is the case. And what it echoes is what happens in in Alzheimer's actually, where that is also a disruption of the dopamine signalling. You can see the nerve ending here where dopamine is being transported.

In, in an in an endosome, and this protein here, which we'll talk about in a second, alpha synuclein is really, really important in the transport of dopamine. And it's thought that in Alzheimer's, you get a lack of transport of dopamine, and, and that leads, to a lack of dopamine inhibition, and we think the same might be true in horses. So what's new, well, the last couple of years we've, we've had some, a little bit of progress.

Not many people study the actual pathogenesis of PPID, probably because we don't get, the samples, and, and it's quite a difficult disease to study. But Huang looked at dopamine expression in the pars intermedia in horses with different grades of pituitary tumour, so the G refers to the pituitary tumour. And found that dopamine, DA expression was reduced significantly in these high grade tumours.

So if a horse has significant tumour in the pituitary, there's very little dopamine, expression there. What was interesting was that dopamine receptor, so the ability to detect the dopamine was not altered actually, and was actually slightly increased in the tumour. Probably because it had bigger, more cells, but.

It's not the fact that you can't detect the dopamine, it's the fact that the dopamine's not there. And that's really important because what Kwang was arguing in this work was that this means that dopamine agonists are valid. So to use Pergolide, which acts on the dopamine receptor.

To mimic dopamine. It's a dopamine receptor agonist. That's valid, because if it, if we'd lost the dopamine receptor expression, then why would Pergolide work?

But what Huang showed was, we've got a loss of dopamine, but not a loss of the dopamine receptor, and therefore Perglide is, is, is worth using. And then we don't need to understand this electron micrograph. I, I can't pretend I do, but, Fortin, has done some lovely work, on the horses as a model for Alzheimer's disease and a model in this, misfolding of the alphas and nuclein protein.

And I remember from the last slide I said that this protein is involved in moving dopamine around and getting it to the nerve endings. And what he showed, what they showed was that in horses with pituitary parts intermediate dysfunction, this particular protein is misfolded. So that means it might not function as as well.

And C panel is, is, is an EM showing, highlighting misfolded alpha synuclein. You don't need to understand it, but believe me, it's a, it's a beautiful paper and and a really elegant work. And so when we're talking to owners, I think we can give them a bit more information now that we think that the dopamine can't be transported very well, to the end of the nerves.

We don't know what causes this at all still, and they don't in Alzheimer's, possibly oxidative stress. Well, it comes with ageing. It could be a natural ageing change.

Certainly, PPID is a disease of the aged horse, or it could be some other toxic insults, that we still don't know. We also still don't know if, if it's the same in every PPID horse. But what we can go back to owners and say is, look, they can't, they can't transport this dopamine, so what Pergolide does is, is take over the action of, of that dopamine and try and inhibit the cell growth and the production of hormones.

And this, I don't really know if I should put this in in pathogenesis, but there's certainly been a lot more interest recently in the different clinical signs we see and a lot of interest in muscle muscle atrophy. And this is a nice grading system that Herbstadt I published, which I. I thought would be nice in terms of, our communication with owners when we're talking about the clinical signs, of Cushing's disease, as distinct from ageing potentially.

And, and do we really pay any attention to muscle atrophy? It often is something owners report, especially this top line. This grading system used lots of different muscle areas, and I'd encourage you to have a look at it, but I just quite liked this grading that they'd used of the, of the top line here, .

Because, it, it gives us kind of a pictorial way to communicate with owners about how the back muscles are, are reducing in PPID. Now the pathogenesis of of muscle atrophy in, in human Cushing's is very straightforward or dog Cushing's is very straightforward. You've got a high cortisol level and cortisol breaks down muscle.

And in in horses we talked last time I did an update about my work, which is on the paradox of PPID where actually you don't have a high cortisol in the blood, but you do have a high cortisol in the tissues. I've yet to look in muscle, but, it makes sense to me that you might have a high cortisol level in the muscle and that will be breaking down the proteins so that you can get more glucose, which is the aim of cortisol. So I just think it's quite interesting, and could be a nice tool for owners to get a grip.

On, on muscle atrophy, but is it a tool for diagnosis? Probably not. Is it a tool for monitoring, possibly yes, in terms of is the atrophy getting worse, and it's something tangible that the owner can maybe scale.

More difficult is the horses, has got hypertrichosis and is very hairy, I think. And more difficult again, if the horse was quite obese when they began, showing signs of Cushing's disease. So it's some difficulties, but it will be interesting.

What I don't think it's gonna be is a very good tool for determining the response to treatment. Because the more recent work has showed there's no real effect of perli on muscle atrophy. So this same work showed that there was an effect on insulin dysregulation, but not particularly on muscle atrophy.

So that's important because when we're talking to owners, we can say muscle atrophy might not, might not come back, you might not get the muscling back. To be honest, they didn't combine that then with a, with a targeted exercise regime to increase muscle, but per glide isn't expected to have a huge number, a huge effect on the muscles. This graph that you can't really see that well, .

Is just the three different scores, that, Herbst used in their paper of of the scoring system, so neck atrophy, back atrophy, and hind atrophy, so rum atrophy. And all you need to know is that the, this is different people scoring different, different horses, but the darkest bars here are your PPID horses. So.

They scored the highest, over multiple, observers. A, A, C, and B are, AC, and S, are observers. And they scored the highest, in all categories.

So, it's something to look at in terms of neck atrophy and rum atrophy as well, and not to just, just focus on the, on the top line. So I think that's quite important. So diagnosis, what's new?

Well, I haven't recapped diagnosis because it's fairly straightforward now. We either tend to do a basal ACTH or we go for a dynamic test, which the test of choice at the moment is a TRH stimulation test where you give TRH and then measure after 10 minutes. But a basal ACTH has become fairly routine, certainly as an initial screening test.

And what was nice to see was a meta-analysis, which we don't see much in, in veterinary medicine, but a meta analysis of ACTH as a diagnostic, by Mayer in 2020. And this is again a complex paper and and demonstrates that. Our reporting in researchers can be poor and limited and, and we sometimes do ourselves a disservice by not referring well to other papers when we're then setting up our new studies.

And apart from that, they concluded that in horses that look like they've got Cushing's, ACTH is a good ruling. So you see a horse that has clinical signs, then ACTH is a good test. But if the horse does not have clinical signs of PPID, then the false positives and false negatives, but mainly false negatives are really high.

So it's important to look at the horse, and not just at the blood, . And I suppose that comes down to our lack of understanding of the different pathogenesis of PPID. So if there are different subtypes, then what we call a horse that looks like it's got Cushing's, as in it's very hairy, it's got muscle loss, it's drinking a lot, it's peeing a lot, it's got laminitis, it's in dysregulated, then ACTHES is likely to be high, but in, in a horse that just has some poor performance or .

Some more subtle signs, maybe some subclinical laminitis. It's really not that great, so we should be thinking about using dynamic testing. The other thing that came out, was that donkeys and ponies aren't horses.

We probably should have known this by now, but, Humphreys demonstrated that donkeys have higher circulating ACTH but they they do show similar circanal variations, so higher in the autumn, compared to the rest of the year, . Always important with donkeys to remember that they're not horses, and we do need to adjust our reference ranges. So that, for me, is to say, make sure you tell the lab that it's a donkey, so that they don't automatically use a horse reference, but that we also might need to use some of our own interpretation when we're, when we're looking at donkeys specifically.

Another useful study that we, we was, that was published, not me, but was published, was that sedation with omidine and borphennol doesn't seem to affect basal ACTH so. The typical scenario where you've gone to dental a horse, and then as you're dentalling it, the owner starts to describe various clinical signs to you and you think, oh, I'm a bit suspicious of Cushing's here. You could probably get a basal ACTH, particularly if it has signs and you've got that higher, predictive value.

You could probably get an ACTH if you've, sedated with Do and Taub. But it will your response to TRH, so you couldn't do a TRH stimulation test. It, it, it accentuates, all of the effects of, of TRH.

I, I don't know the pathogenesis of that. It's probably to do, with your alpha 2 receptors in your pituitary, but again, it's useful to know that if you are sedating a horse, you could still do a basal ACTH and it shouldn't have a huge effect. I would caution that you should try and always take your bloods in the same way so that maybe you screen, particularly if you have clinical signs, but then you come back to do a TRH stim if you're not sure.

And then a TRH stimulation test, this was a really interesting study so I haven't put the reference there, but . With a TRH stimulation test, you measure and then you give the TRH and then 10 minutes later you test again. And in this study, they looked at what happens if you test at 9 minutes, which was called early testing or early sampling, and what happens when you test at 11 minutes.

And 21% of the horses would have had a different interpretation of testing with either 9 or 11. So, I've always been fairly relaxed about about that 10 minute window, but it seems from this work that it's really, really important to do it at 10 minutes if you're gonna use the reference ranges. So just remember that and and start a stopwatch and, and try not to get distracted on your TRH sims.

I think that's important, and the reason behind it is probably that. Everything that comes from the pituitary is pulsatile in fashion, so ACTH is released in pulses, and probably the amplitude of the pulses only remains high for, for that 10 minutes and then the amplitude will start to reduce. So 10 minutes is important, minutes matter for a TRH stimulation test.

And then some really cool stuff on MRIs. This was, a nice paper by Hobbs Zel who showed that, you can do nice MRI imaging of a normal pituitary. They haven't done PPID horses yet, but they were pointing out some interesting, factors in terms of shape.

So, this one at the top, and A, they're that kind of classic squashed, shape that I showed you earlier. In the pituitary anatomy slide. Whereas this horse B has a kind of more rounded, sort of semi-circle like pituitary.

Now the limitation of the study with these horses were not euthanized and the pituitary is looked at. So we can't say absolutely without with certainty that the histology was normal, but they had no clinical signs and no biochemical signs. So it's interesting to note that MRI could, could be there in terms of, in terms of diagnostics.

Now, whether your owners will opt for an MRI over a free or cheap ACTH is is another matter, but it is something to consider, particularly if the horses are showing other signs, such as potentially blindness or, or whether the owners are maybe wanting a very definitive diagnosis in terms of where they're gonna breed. From the animal or or whether they're having an MRI for another reason. But I I think head MRI's are gonna be are not gonna be used frequently for the clinical diagnosis of PPID, but it's something to to have a think about.

So treatment and management, well our treatment is, is fairly limited at the moment. We have Pergolide, which, as I said, is a dopamine agonist, so it acts on those dopamine receptors to reintroduce the inhibition to the pars intermedia. And again, we've got a nice systematic review in 2020.

Coming out which was looking at at the actual effects of her glide, despite using it a lot, we don't actually have that much data on, on what it does. So they looked at, these different studies which are along the bottom of this graph here, and overall they concluded that there was a clinical improvement in 40 to 100%. That's quite an interesting figure, because it's, it's quite it can be as low as 40%.

Reduced ACTH in 44 to 74%, so 20 odd will not have a reduced ACTH and return of ACTH to reference interval in 28 to 74%. What all of these tell me is that we have either different diseases or spectrum of disease because. If 74% can not return to ACTH reference interval, they might be the ones that have a true tumour, and we know that Perglide isn't gonna reverse the tumour.

So it might be that you can never get the ACTH level down to reference range, but you can reduce it. And it might be that we're missing different subtypes that don't respond to Pergolide or different tumours that do have changes in expression of, of dopamine receptors. So, I'm just introducing some ambiguity here so that you can understand if you're treating these horses that not all of them will respond and for owners not to be despondent if theirs doesn't.

And also to get you to think about how you view a successful treatment, and whether that's a clinical improvement or a reduced ACTH. Personally, I would go for a clinical improvement and I don't worry too much about the ACTH and I don't chase it. Because I know that a great proportion of them, will not reduce in ACTH, but my question to the owner is, is it clinically better?

And that is more important, so I would, I would caution against chasing an ACTH with ever increasing Pergolide doses. The donkeys featured again in 2022, which is excellent, because it hadn't been number 4, shockingly, but Perglide is bioavailable to donkeys, with oral administration, so that's good to know. .

Blue light therapy, I brought this up, it, it's not a treatment for PPID as shown by Miller in 2023. They've shown that there was no change in ACTH with blue light therapy. The reason blue light therapy has postulated as a treatment is because the pars intermedia is seasonal in its effects, so it's preparing the horse for winter and it expands in the autumn.

That's why everything is increased in the autumn because it's getting ready for winter. So it's responding to changes in light levels. And thirdly, we know that light levels affect hair coat in horses, and what Miller's study was doing was looking at whether it blue light therapy can change ACTH but also whether it can alter the hypertrichosis phenotype that you get.

They found some slight changes in hair coat, so it might be useful for hair coat, but it definitely doesn't, treat PPID in any way, just in case owners bring it up as as something they've read about. What we do know, and we knew before, but we know even more now, is that determining instant whether instant dysregulation present is present is crucial to the management of PPID. So about 50% of horses with PPID will develop laminitis.

And that 50% are those ones, with, with instant dysregulation. So, really, if you were picking what to test on a horse with suspected Cushing's, you could get away with using your clinical judgement in terms of looking at the horse as to whether it had Cushing's, and I would spend the money on determined. Whether it has insulin dysregulation, because that's ultimately what's life limiting in terms of laminitis.

So that's really key. I don't think we should be seeing any horses with PPID and and not at least talking to the owners about quantifying laminitic risk by looking at insulin dysregulation. There is some correlation between ACTH and insulin dysregulation, particularly in the autumn, but it's not a direct correlation, and it's possible that we're not actually measuring ACTH and possible that we're measuring clip, which we know influences insulin.

And this comes to the latter point. When I talked earlier about the POM C peptides, this very long peptide being cleaved into lots of smaller ones, those cleaved products are all really similar to each other. And when you design a test, like an elizer or an immunoassay, which we use to measure ACTH, it's not always that specific.

So there'll be big overlapping chunks there that that might be picked up by an ACTH elizer, but they might actually be clip or beta endorphin. or ACH or alpha MSH, and there's a lot of correlation between them. So Ed Knowles has done some interesting work, looking at at what we're actually measuring, and there is cross reactivity with some clips, so.

That's again just introducing some more lack of understanding of what we're actually measuring when we say we're measuring ACTH. And sometimes you might be thinking you're measuring ACTH, but you're measuring something different and therefore, the horse isn't responding as you thought it would. But the take home from this is, if you see a horse that you suspect has PPID, please, please, please determine whether it has ins in dysregulation or not.

And the final thing I've got about in terms of PPID is this great work that was done to determine what the research priorities were, what we don't know. And I think this is sometimes a bit shocking, to, to vets and certainly you see a lot of PPID cases and, because there's so much we don't know. For example, we don't know.

In horses receiving treatment for glide, if the laminitic risk is reduced, and we're asked that by owners all the time, and we really don't know. We don't know about disease progression, we don't know about stress or pain on the reliability of accuracy of diagnostic tests. And we don't know what to do if the maximum dose of per glide has been reached, but hormone levels are still elevated, and that's probably because we don't know enough about the different types of disease.

So it's a strange note to end on in terms of discussion of PPID, but I think it's important that we are honest with the with owners and also that as vets we, we lobby for these some of these questions to be answered because they're really important. And hopefully when I come to update you maybe in a couple of years we might have have have had a go at answering a few of them. So I'm gonna move on to equine metabolic syndrome, what's new.

So we still define it as a collection of risk factors including obesity, instant dysregulation, and genetic predisposition, which results in an increased susceptibility to laminitis. We're still using this definition. There's some debate about whether we can use the term EMS and insulin dysregulation interchangeably.

I think insulin dysregulation is a critical feature of EMS, but some argue that obesity isn't always a feature. Now this is a quite a controversial topic, I don't know why, but some people argue very strongly that they see lean horses that have insulin dysregulation and therefore obesity can't be in the, in the EMS definition. I think that it could certainly be a geographical thing.

Certainly people in the states seem to report this a bit more than in the UK. What I see. Are what we call toffees, so thin on the outside, but fat on the inside.

So they might look thin or they look like they're not obese. But when you scan them, or when you postmortem them, sadly, you see a huge amount of intra intraabdominal adipose tissue. So I would caution, against, if you have a horse that's laminitic but doesn't look obese, it doesn't mean it doesn't have equal metabolic syndrome.

I would still test for instant dysregulation, and I would counsel owners that fat can be hidden. Literally all of our scoring system for fat, in horses is done on subcutaneous fat. And we know in humans that that's not even the dangerous fat.

You're pretty safe if you have it subcutaneously, is if you have it viscerally that it's really bad. And now we just assume that if you're fat on the inside, you've also got visceral fat as as a horse, but that's not always the case, and vice versa. If you're really struggling to convince Noa, then I, I certainly use abdominal ultrasound just on the ventral abdomen to, to see if there's a lot of intraabdominal fat.

This is something that's gonna be a hot topic for discussion going forward, but just to think, is this horse thin but actually does it have lots of fat inside, or could it still be insulin dysregulated for another reason? So prevalence updates, so, Harry Karslake did some really nice work on a UK population. We didn't actually, surprisingly, we have very little prevalence data on actual EMS despite us all saying it's very prevalent.

We had a lot of obesity prevalence data, which I've presented before, but prevalence of EMS hadn't really been reported very well. So we're now sitting at a prevalence of about 23, 24%. Which seems about right.

And I've, I've just drawn attention to some Iranian data as well, which, sits there as well, around 14%, and they had obesity in 25% of their horses at pasture, but those are not a pasture, only 9%. So that's a bit more obesity data and they've also added a little bit of EMS data. The problem always with prevalence data or incidence data is that The definition can be can be debated so it's always important to look at the criteria, but.

I think that this fits with our clinical, our clinical feeling that, in the UK we've got about 30% of horses are overweight or obese, 30 to 40%, and about 20 to 25% have EMS. So that's, that's an interesting fact to tell your owners and, and we'll surely get some more prevalence data, from EMS soon enough. So pathogenesis, I'm just gonna do a quick recap, which is almost impossible to do a quick recap.

I could spend at least half an hour telling you what we don't know, which is where all these question marks come from. But we know that there's a genetic predisposition to EMS, so that's native breeds. We don't know.

We still don't know what the genetic predisposition is to, so we don't know if it's to becoming obese. We don't know if it's to becoming insulin dysregulated. We don't know if it's something, inherent in the liver or the pancreas or the adipose tissue.

We don't know any of those, but we know there's a genetic predisposition. It's possible that it's similar to dogs and that it's a predisposition to, food motivation. So our native ponies very food motivated and therefore more likely to become obese.

We don't know. We know that obesity and adipose dysfunction happen in EMS and we know that as a horse gets obese, there adipocytes, which you can see in this panel. Down in the corner here, the adipocytes get really, really big, and they're called hypertrophied, and, and they're really unhealthy.

And I published that data a while ago now, so it's not really new. But we know that that adipose tissue will then feed into the insulin dysregulation, in the other tissues. Now, the insulin dysregulation, I'll talk a little about, in the next slide.

As well, but we don't really know what it means in horses or how it occurs. No, we don't even know in humans, to be honest, so, and there are so many theories, and again, like PPID, it's likely that there are different disease types happening. And that some horses will have alterations in the gut, the absorption of glucose, and that just regulates their insulin.

Some will have true muscle insulin resistance. Some will have different, effects of fatty acids in the liver, which will produce in liver insulin resistance. Some will have all three, some will have a 2 combination.

What we don't know is how to distinguish them in, in the living animals. Even in, even in postmortem samples, we really struggle. To determine what's an insulin resistant tissue and what wasn't, and also what came first, because by the time you get samples, that animal is insulin dysregulated.

So we don't know what triggered it. In my mind, the obesity triggers it, but still there's missing gaps there. And what we really don't know is how the instant dysregulation results in laminitis.

So I feel like this talk is mainly me listing things we don't know. But just so that you can have confidence saying to owners, we really don't know this, it's fascinating, but we really don't know. We know that if you infuse insulin at High enough values, you can induce laminitis in an otherwise healthy horse.

And that's how I would say it to owners. We don't quite know how we get from being a fat horse to being, an instant dysregulated horse to being a laminitic horse. And I'm not gonna talk about that particular bit today because I haven't got time.

But it's, it's, it's an area that we will be following, closely over the next, few years. So just briefly on insulin dysregulation, these are the current thoughts as to what's feeding into ID, so instant dysregulation, chronic inflammation, particularly from the adipose tissue, ectopic lipid accumulation, so lipid in the liver, lipid in the muscle, lipid around the heart. An abnormal lipidome, so a different way of processing your lipids.

Gastrointestinal hormones, which I will come back to, cos that's been a particular area of interest in horses recently. Cortisol dysregulation, which is what I study. So we know that horses that are obese are cortisol dysregulated.

They have more cortisol, they have higher ACTH and they have higher cortisol in their tissues. We know that cortisol activation induces insulin resistance in tissues, so that's certainly one, something to think about. And definitely something to think about when you are managing horses with laminitis.

You don't want to stress them out if they're also insulin dysregulated. You don't want to elevate their cortisol levels because that will only worsen the insulin dysregulation. Something to think about if you're managing them in a box rest and they're, they're hating it because they're not used to that.

And then oxidative stress, which seems to be a common pathway in most, most diseases. So I won't spend too much time on this, but the interinsular axis, you will, hear about a lot. So predominantly talking about two incretins, GLP1 and GIP.

They both have, so they're basically released from the gut, on, exposure. On, on food absorption, and they have direct actions on the islets of allowing your hand to induce insulin secretion. So it makes sense it's a good system.

You get glucose being absorbed in your gut and your gut tells your pancreas straight away, so you don't have to wait for for the glucose sensing to happen. GLP one also impacts gastric emptying, satiety particularly, and glucagon release, and GIP promotes energy storage through direct actions on adipose tissue. So the work that's been done so far is horses definitely have a functioning interinsular axis, and there's a little bit of data, this is relatively old now showing that there's a correlation.

Between body condition score and cresting score and and GIP and the other increins. So it looks like horses with obesity have an activated interinsular axis. Now, how that impacts the disease, we don't yet know, but just remember this because we'll come back to this slightly when we talk about pharm pharmacological interventions.

And then just a very brief recap on how does insulin dysregulation present in horses. Well, we have a, we can have any combination. Again, I don't think it's one disease.

It's probably a whole spectrum of diseases, but we can have horses that present with basal hyperininemia, horses that present with an abnormal post-prandial. Increase in insulin and horses that present with whole body insulin resistance, and horses that present with all three or with any, any combination of the three. So let's talk a little bit about what's new in the pathogenesis.

What we, we're not making great strides, but there's lots of people trying to do lots of things. So there's some nice work, . On the the Lipidome and the metabollo, as potential pathophysiological markers and also biomarkers.

So we know that now the instant dysregulation laminitis risk was associated with alterations in the glycerin phospholipid and glucose metabolism. So this is, well, you could view this in two ways. You could view this as a, as a little glimpse into the what's going on in terms of.

What's triggering the insulin dysregulation, but also could these be new biomarkers? Work from, from my lab, by Miranda Doy showed that plasma vitamin D, which is, classically low in humans with obesity, is actually higher in obese in dysregulation, disregulated horses. So when owners ask you if vitamin D supplementation would help their horse with EMS.

Probably the answer is no, because they've actually got quite a lot of it circulating. But we're now taking this work on to look at the role of adipose in the storage of vitamin D, and what's going on. Are they just not able to store it in dysfunctional inflamed adipose tissue.

So it's an interesting question, and when you might get asked by owners, but at the moment, the jury is slightly out, but it doesn't look like they are, low in vitamin D at all. The supplementation's probably not necessary. This work from Macron in 2022 showed that instant dysregulation horses seem to have a threshold for non-structural carbohydrate, content of a meal.

So. NSC didn't see a particularly big response to insulin, but horses with insulin dysregulation, once it tipped over the balance of 0.1 grammes per kilo body weight per meal, there was a huge rise in insulin responses which you didn't see in non-insulin dysregulated horses.

So it's not like it's a linear response to how much non-structural carbohydrate or sugar you've got in in the grass or the forage or the meal. It's like it's a two wave, so you're OK, you're OK, and then suddenly it increases and the horse is not OK. And that could explain why a flush of grass, a sudden intake of lots of sugar will spike your insulin, a horse's insulin and cause a lamintic episode a lot more.

This is really nice work, and it is on the pathogenesis because it's about risk factors, and about how horses become fat. And I'll come back to Tamsin Furtado's other work. She's, she's been very productive the last few years and has produced some excellent work.

She looks more at the sociological, aspects of obesity in horses, and in this paper she describes the obesogenic environment of the livery yard. So all the impacts on the horse's weight, including. Other people's opinions, the actual nature and setup of the livery yard, the conceptual model of, of how the horse and owner interact, showing that the owner influences the horse, but is also influenced by lots of things like the environment, the social norms, the yard manager, other people on the yard.

Now this is something that any vet could probably tell you, but she's really nice. Depicted it in this kind of and described it as this obesogenic environment. So when we talk about humans living in an obesogenic environment, we talk about things like chocolate being available when you're at the checkout, in the supermarket, and that's kind of the obesity and fast food adverts everywhere.

For the horse, the obesogenic environment seems to be more how the livery yard operates around food and how Horse owners, the food in their relationship with their horse with food. Really interesting read. It gives you a really good insight into, into what owners are struggling with, especially when, you know, we say, right, this horse has to lose weight.

Just remember that there are layers of, of restriction on these owners. And, and I'll talk a bit more about Tamsin's other work later. One interesting, side area in the pathophysiology or the pathogenesis of EMS has been the cardiovascular effects research that's coming out.

So, some nice work from Williams, a pilot study, very, very small study, but showing that decreased insulin sensitivity correlated with alterations in both systolic and diastolic function, which is very interesting. Ben Sykes' group showed that these horses that are in deregulated are also hypercoagulable. So interesting if you're putting cannula, catheters in them for long periods of time.

And then, work from definesca showed, that ingesting a high energy diet first induced minor changes in blood pressure, but progressed to left side of cardiac hypertrophy and Shetland ponies. So. I think it's important to point out to owners, and we often use the similarities between human metabolic syndrome, where the outcome is cardiovascular disease, heart attacks, stroke, we say all the outcome is laminitis.

We don't know how much the systemic cardio. Vascular effects are impacting the blood flow to the foot, but it's important also to say that these are systemic effects. The the blood, the blood vessels and the feet are not going to be the only ones affected.

I've certainly certainly shown shown in the past and research I've published that they have, Endothelial dysfunction throughout the whole body, all the way up to their facial vessels. And, and now we're seeing that there's changes in blood pressure and effects on the heart, which makes sense. There's no reason why the horses should be any more protected.

Probably what we don't see is major damage or major heart disease because horses don't live as long as humans, but it's something to bear in mind and something to, to keep an eye on. So in terms of diagnosis, well, at the moment, just to recap, we probably have a basal insulin as our go to, and then either an oral sugar test, an oral glucose test, so you could give carrot syrup light and then . And then retest insulin after a basal insulin, or you could do a combined glucose insulin tolerance test.

There's lots of talk about cutoffs, but I just threw out some interesting things in terms of, Ed again, Knowles has shown that insulin at baseline. Or at T60 after corn syrup was the best way to quantify future laminitis episodes, in, non-laminitic courses. So this is really interesting in terms of why we're testing for insulin dysregulation, and I think one of the main reasons is because we want to, we want to quantify laminitic risk.

And then some work, from Finland showed that the oral sugar test doesn't really vary with season, but interestingly that individual horses will vary quite a lot. And to me, I interpret that as for the clinical approach. It's OK to go back and test again.

So just because one last year you tested this horse and it's or sugar test was fine, doesn't mean that 6 months later or a year later, it's, it's still gonna be fine. Or even if you test it 4 weeks later, it's still gonna be fine. Horses are quite variable individually, so that's quite interesting, worth repeating.

Management, what's new. So again some work from my group, we showed that straw supplementation was a really in, in fields in winter, was a really, really good way to induce weight loss. So we supplemented horses with either hay entirely, so that's Group B in this graph, or 50/50 hay and straw, and saw a significant weight reduction in the hay and straw group, but still maintained their browsing behaviour, .

We didn't see any side effects of feeding straw. It's cheap, and if, if you're supplementing forage on the field in the winter, straw, a 50/50 straw, supplement would be really, really good. I also include straw in horses that are being box rested and are being dieted in the, in the stable and are.

Eating their, their one small hay net really, really fast. If you include straw in that, to just either add a bit of extra straw or take some of the ration of straw, they chew for longer, they work their way through the straw to find the lovely bits of hay, and then when they're hungry, they'll eat the straw as well. So I, I think it's really something to think about in terms of your management of these horses.

This work from Sip Thorpe was really nice. It showed that even a tiny amount of additional carbohydrate each day can cause a measurable change in the axis responses, intrainsular axis response to eating. So the take home from that is cut out the treats.

So what owners think is OK is probably not OK in terms of, that, that one little treat, that one carrot or that one apple, it will change your whole gut, instant access. And coming back to Tamsin Furtado's work, I'd really encourage you to look at this. This was about human behaviour change and equine obesity, and how different components of behaviour influenced the recognition of equine weight and also the management of equine weight.

So she's listed the barriers to weight management, the owners come across. So there's some interesting ones like the physical having to physically soak hay and bring a a soaked hay net out of a bucket of water can be a barrier to some people soaking it if they don't feel physically able to do it. Or social norms which promote fat as part of a healthy equine body, so in magazines or show classes.

Familiarity with familiarity with the horse really impairs ability to see obesity, and it can impair their knowledge of the health risks of obesity, so they can objectively see that they are health risks, but then they're so familiar with their horse, they don't then reflect back on that. The key with this is that we have to understand the barriers in order to help our owners. So it is no longer good enough for vets to just say, your horse has to lose weight, you have to do this, this, this and this, and then to leave.

We have to talk to these owners in detail about what's stopping them, what could be difficult, how we can get around it. There is always a way around. Some point it might be, you have to change livery yard or you have to move, .

But other times it's just about changing the way they think maybe and all, but the key to that is understanding where they're coming from. So education or enforced education on owners is not sufficient anymore. We need to understand the barriers and then address those specifically.

And and I'd encourage you to look at this research because it's, it is really, really interesting and can really change the way we we impact horses with obesity. And I've just then got a couple of slides, on pharmacological interventions. I won't spend too much time on this because I would caveat it all by saying that it is no, substitute, for, for good weight management, for a good diet and exercise.

But just because you'll come across them, there's drugs that are targeting targeting the enteroinsular axis. So GI sorry, that's just a GLP one antagonist agonists. So GLP one increases insulin resistance release, as I said earlier, you'd expect agonists to exacerbate the postprandial hyperinsinemia, but actually in humans, it's those off target effects, so slowing gastric emptying, decreasing glucose absorption, and changing satiety, which really do seem to have an effect.

So, semaglutide, is now licenced in humans with some really good effects in some. There's a little bit of data in horses, cematide, slightly decreased insult in response to carbohydrates. Very small numbers, we're not there yet.

There's some quite significant gastrointestinal and thyroid side effects in humans, very little data in horses, and there's very little safety data, and they're not licenced, but there's something to think about only as a last resort. And SDLT2 inhibitors we know even less about in horses. The increased glucose discretion by the kidneys, so then lower insulin secretion by the pancreas.

Doesn't make a huge amount of sense because horses don't tend to have hyperglycemia, so they're, they're useful in humans with hyperglycemia. But not necessarily in horses because hyperglycemia is rare. They have lots of off target effects on the heart, and the kidneys, and in humans, a big side effect is urinary tract infections because you're increasing the glucose, extraction from the kidneys.

So you're putting glucose into the urine, which is a . A bed of of bacteria. Very, very little data in horses.

There's one case series in Eve, and there's no safety data. So I wouldn't recommend using them until we've got more. So that in terms of pharmacological treatments, the news is the old news that pharmacological intervention is not a good substitute for diet.

And exercise and supporting your client, if you're gonna change the way you manage these horses, I would spend more time and charge them for your time in terms of really understanding how, how the client is, is, is feeling, and what barriers they might have. So I would only consider pharmacological treatments in truly refractory cases. And consider them very carefully given the lack of evidence and safety data and also consider consulting a specialist.

I think we don't probably, or maybe I'll just say this because I am a specialist, but we don't necessarily as much as we should for endocrine cases. Thank you very much for listening. I'd like to thank my, funders, that's the Wellcome Trust, but also Plan and BBSLC, and it's been a pleasure to talk to you today.