So good evening everybody, and thank you very much for joining us for tonight's presentation on what's new in equine Endocrinology, which has been presented by Ruth Morgan and is very kindly sponsored by Bailey's Horse Feeds. Ruth graduated from Cambridge University in 2006 and then having spent 2.5 years in first opinion equine practise, she undertook a residency in equine internal medicine.

At the University of Liverpool, during which she gained her Royal College certificate in equine internal medicine. In 2012, she started a four-year PhD in equine endocrinology at the University of Edinburgh, focusing particularly on laminitis caused by equine Cushing's disease or equine metabolic syndrome. In 2013, she gained her diploma of the European College of Equi Internal Medicine.

She completed her PhD in January 2015 and is now a Wellcome Trust Clinical Research fellow in equine Endocrinology and an equine medicine clinician running the University of Edinburgh equine Endocrine clinic. So if anyone has any questions to put to Ruth, if you type them in the question and answer box, and then we'll put them to Ruth at the end of the presentation. So over to you.

Thank you very much, Caroline. Yeah, and, welcome to this, talk on equine endocrinology. It's gonna be, a little bit different, maybe from endocrinology, CPD that you've been to before.

I'm trying to focus more on the pathophysiology and the research that's going on in that, mainly because that's where it's really getting exciting at the moment. And also because, it's something that as vets, we don't always get exposed to, on a regular basis. So, hopefully it'll be of interest, but I'm happy to take questions on more of the practical aspects and the treatments, and, and clinical side, at the end, that's absolutely fine.

OK, so, yeah, as Caroline said, I'm Ruth Morgan, and I'm a, I suppose I call myself an equine endocrinologist, and I have a special interest, particularly in, leukocorticoids, so. So, so in today's lecture, we're gonna talk about equine metabolic syndrome, the pathophysiology, behind equine metabolic syndrome and equine obesity and insulin dysregulation. And then a bit about pituitary powers intermediate dysfunction, going back to some of the basics of anatomy and physiology, and then also.

Looking at cortisol and equine endocrine disease and then finally, rounding off with some discussion on, endocrinopathic laminitis and the links between endocrine disease and laminitis. So, equal metabolic syndrome, I stick with this, definition still. It, it has been questioned a little bit, but, I stick with the definition that it's a collection of risk factors, including obesity, insulin dysregulation, and genetic predisposition, which results in an increased susceptibility to laminitis.

So this is a human with human metabolic syndrome that is defined as a collection of risk factors including obesity, insin dysregulation, and genetic predisposition, which results in increased susceptibility to Cardiovascular disease and diabetes. And this is our classic and equal metabolic syndrome, pony. So that's why I, I kind of stick with this, definition.

It's not a disease per se. It's a collection of risk factors, and laminitis is very much a symptom, and an endpoint. And really, what we should be aiming to do is, is pick up equal metabolic syndrome before laminitis, happens.

And also I'd say that I always include obesity and equine metabolic syndrome, and some people don't, but we can talk a little bit about that in a, in a second when we talk about measuring obesity. So let's talk about obesity. One of the, defining features of equine metabolic syndrome, it's defined as an abnormal excessive fat accumulation that presents a risk to health.

So that's a really important aspect of it. It's not just, being overweight, it's to the extent that the adipose tissue is unhealthy and now presents a risk to your health. So in humans, it's about 1 in 4 adults are classified as overweight or obese, and about that equals about 124 million people, which is quite extraordinary.

In horses, we've got some nice data showing that, anywhere, between 24 and 40%, but Most of these, studies are of ponies or at-risk breeds. So that's, that's an overexaggeration if we included all of our thoroughbred racehorses, they would not, as we've seen in the Australia study, they're 9.3% in the horse.

So we know there's a breed predisposition. So how do we measure obesity? Well, the problem with the main methods of measuring obesity in humans, for example, like a BMI, which has recently come under question, but we have so many different breeds that we couldn't apply a BMI particularly to this Clydesdale and this Shetland.

Away bridge equally is limited because we don't know what the ideal weight of a, a cross between, a, a Welsh pony of unknown origin and a thoroughbred, for example. We don't know what the ideal weight is, and we can't scan them generally to determine where the adipose tissue is laid down, so it has its limitations. And so do to weight apes.

So weight The tapes were, designed to be used on your classic, probably warm blood, probably kind of lean, warm blood and not on your rotund, Shetland pony or your dip back, Arab, or with different body shapes. So we come up, come up against a few hurdles before we We even defined, how we measure obesity, and that is a problem. So more and more, we're using the anthropomorphic measurements of body condition score.

I teach clients, the 0 to 5, the Caroline Huntington, but certainly on for my research, I'd use the 1 to 9, and this is a slightly modified 1 to 9 of the Henneer body condition scoring system. And what they do is they take into account the fact that adipose tissue is laid down in different places and different horses, and not all horses will have adiposity everywhere. So I think they're really important.

They have their flaws, they're not always great, particularly the income in, the inclusion of the net crest, which we'll talk about in in a minute. But they have their place, and you can definitely teach owners the 0 to 5 scale. And there's, there's an equine Body Condition Score app, which, you can get owners to use as well.

I think it's important for owners to be able to do this, but also vets. I think we're really bad at it, and particularly if we only see certain types of horses or ponies all the time. So it's really important to, to test yourself on these.

When I'm seeing horses in my clinic, I do several other measurements of adiposity. So I, I do, heart girth, belly girth, and rump width, and I think that just adds a bit of objectivity to the body condition score that I've given. And tries to take in the adipocity that we can't always, quantify in a body condition score and certainly on a way bridge.

So, you often get fat pads around the shoulders, which the heart girth should take into account. And often you get a large rump, and, and the body condition score doesn't always take that into account if there's not a big ridge down the back. I also do, body length to heart girth ratio, and I think that's quite useful, to take into account the kind of, short stature, and, breeds like the Exmoors and the Welsh ponies.

And I also measure adipose tissue by ultrasound. And I think that's really Really, really useful. And it's a bit counterintuitive, because normally when we're ultrasounding, we're desperately trying to, get rid of the adipose tissue and, and, not let it interfere with our, with our image of the intestines, normally, or, or the heart.

But, in this case, I like to measure it and, I like to Present owners with how much that is, because often, especially in horses that maybe have Cushing's disease or maybe carry their weight in different places, it can be really hard to communicate obesity to owners. I think that's one of our main jobs in tackling equine metabolic syndrome is to find new ways to, to communicate obesity and and allow owners to see their horses the way we do. Because I think body dysmorphic disorder is a significant problem amongst our horse owners.

And, and that's been shown in several really nice studies. This one at the top, showed that if you've got like a perfect body condition score, say this one in the middle here, you get a really high, and this one, you get a really high, rate of, sorry, this one up here, and 95% because it's nice and lean. People can see leanness.

What they can't see is obesity. So, and, and especially when the colours are different, or when, the horses, is an odd shape. So that's what this study showed.

And then, then there's another study exploring horses owners' understanding of obese body condition, which I'd encourage you to go and look at. And it's, by Tamsin, Furtado, at, at Liverpool, and it was a really nice paper. Look at the barriers and the, The opinions and the thoughts of owners on obesity and, and how, and it gives us tools as vets to allow us to communicate with owners.

And I think the the important thing. Just like weight loss in humans is that there's often, a denial stage. People aren't ready to make the changes or willing, and sometimes you need to just accept that and wait for the owners to come on board.

And sometimes sadly, it takes what, Tamsy Furtado. Refers to as an awakening event, such as a laminitic episode, to get the owner on board. And, and that's, that's heartbreaking for some of us, but if we can look at this research and really take on what the owners are saying to us.

So there's a couple of quotes there. I thought that was just her build, thought she was just a big chunky cop. And, and that's what, that's what we're up against.

And, and that's not an owner that is in a huge amount of denial. They just think that that's what their horses always look like and that's how their horse should look like, because that's how all the other horses on the yard look like. So it's, it's a really interesting paper.

I'd encourage you to, to, have a look at that. It's very recent. So I also do the Netcrest score.

I think that's really useful. Netcrest has an independent association with insulin dysregulation, and it's a specific area, of interest, but I also make sure I look at the rump and the tailhead. Netrescore can be a little bit deceiving, particularly in horses that have been very, very fat in their time.

And I will talk about this a bit later when I talk about the histology of adipose tissue. If horse has been really, really fat, then they've often laid down a lot of fibrous tissue. And so, the shape of the neck crest never changes.

And that can be really disheartening for owners if that's what you're going for. But certainly owners will tell you, that the, the texture of the neck crest changes, and that's something to be aware of. But it's not necessarily the most important adipose depot, as we'll talk about later.

So why do horses come obese? Well, it's not rocket science. They eat too much and they don't exercise enough.

They can eat as much grain and grass as they like if they're desert orchid here and training, a high-level training, and they also have got the genetics of a thoroughbred racehorse. But if you've got the genetics of a Shetland and you're eating this rich grass and supplementary feed, then the calorie intake is going to far outweigh, your calorie output. And I think that's not just as simple as it sounds because we have had repeated fertilisation of our grass, certainly in the UK.

And that, therefore, has made it an uphill battle for owners, in terms of, having horses on grass and keeping the weight down. So this Shetland pony is meant to live in Shetland Isles, where you get, a, a cyclical change in the amount of sugar in the grass. And, and that is a lot less the further south you go, and when you're on fertilised pasture or Managed pasture as opposed to, to the hills.

So it is an uphill battle. I think that's important to talk to owners about, about it, it's not it's not necessarily, that you're doing anything wrong. We are fighting against both the genetics and the grass.

So let's talk about genetics. So we all know that there's a breed risk for obesity. I don't need to tell you this.

We've got this Welsh car, this grey Welsh cob on the left, and his thoroughbred mate on the right. And that's laddie, and he had laminitis so badly and severe instant dysregulation. And he was managed exactly the same as his thoroughbred friend, and yet that thoroughbred never had any, any issues.

So there is definitely a breed risk. Within a breed, there's an individual risk. So this is a herd of ex small ponies, and within that herd, so compared to thoroughbreds, there are more at risk, but also within the individuals, some are more at risk than others.

And I think there's a familial risk, but there's a lot less evidence for this. So, the familial risk comes from either, the genetics of your, of your parents, or the epigenetic factors that happen in utero. So there's some really interesting work on, women with gestational diabetes, They are more likely to give birth to children who then go on to develop diabetes.

But equally, the other extreme, women who've been subject to starvation or malnutrition during pregnancy are also more likely to give birth to children who then become diabetic, or obese and diabetic as they get older. So it seems like any extreme in utero, so extreme obesity or extreme man. Nutrition can result in an increased risk of instant dysregulation, certainly in humans.

We don't have any data in in horses. we probably do, to be honest, because we probably have the stud books, and if you ask breeders, they'd know, if you breed it from a fat mare, you get a fat pony, a fat, offspring, but we, we need much more. So what are the genes determine?

Well, that's a really important question to ask because it's not, it might be being overweight. It might be an appetite thing, which I'll talk about a bit later. It might be a less sufficient metabolism of food, or hormonal factors, or it might be that they're more genetically susceptible to the consequences of obesity.

So insulin resistance, which then might lead to more weight gain. So when we're looking for genes, we need to make sure we look at the, the right ones. And I'm not sure that's quite been done yet.

So just to talk you through a little bit more, obviously I've talked about breed and there's an idea that within certain breeds, there's different genes regulating adiposity, insulin signalling, lipid transport and appetite. And there's this thrifty gene hypothesis where we think that, well. It's suggested that horses that are meant to be on very poor pasture have been bred have have selected themselves over time to be more insulin resistant.

So, but within a breed, there are also might be individual single nucleotide polymorphisms or snips conferring a susceptibility, potentially in the insulin, pathways all related to adiposity or appetite. And then as I talked about epigenetics, but we must never forget that it's genes plus environment. There's nothing, there's no, genetic effect really without the environment unless it's an extreme monogenic condition.

So there's been a, there is an ongoing effort to look at at the genetics of metabolic syndrome, and they think they'd found a risk locus in this FA 17A4 gene, which is a bit difficult to, to explain. It's not a very obvious one. And also new data has just found that there isn't a really strong association with it.

By metabolic syndrome. Now, my criticism of these would be that they've gone for equine metabolic syndrome, which is such, even within the experts, well, especially with the experts in the field, there is huge debate over how we define it, how we define it in dysregulation, how we define obesity. So, until we've really nailed those, it's gonna be quite difficult to find the genetics.

So, just a nice story in Labradors, and this is probably what we're aiming for. So this is nice work by Eleanor Rafffen in Cambridge, who found a, deletion in the, PO C, the proopio melanocorticotrophic peptide, gene, which is associated with weight and appetite in Labradors. So she did a great study where she found Labradors that were really obsessed with food, .

And Labradors that weren't so fussed. And she, she measured that food motivation by putting them in a room with a sealed box with a really tasty, treat in it. And the ones that were really food motivated just destroyed the box until they got the treat.

And the ones who weren't sniffed at it a bit, but when they realised it was quite hard work, they, they went off and, and, and explored the room more. So that way she could distinguish. Distinguish between really food motivated Labradors and not food motivated Labradors.

I'm not sure many of us come across the, the unmotivated ones. But in doing that, she then sequenced these dogs, and found, the, a genetic, mutation in the POMC gene, a deletion in the gene, which was associated with, beta MSH and beta endorphin, which regulate appetite. .

So that's, that was an an amazing breakthrough study, and that's what we kind of need to look at in the horse. And in humans, appetite has been the driver of obesity. We've now decided that essentially obesity in humans is a disease of the brain, and it's a disease of appetite.

And everything that comes afterwards, are complications of that initial problem with our ability to regulate our intake. So what about horses? As well, horses and ponies anecdotally have different appetites.

You, you, many of you will heard, owners say, Oh, my pony lives on fresh air, or that they're the ones breaking into the feed bins. Ponies can eat about 5% of their body weight in grass as dry matter when they have 24 hour access to pasture, whereas horses choose to self-regulate and, and eat around 2 to 2.5% of their body weight.

And also, if ponies are restricted in their grazing and only allowed to only allowed grass for 1 hour a day, they adapt to consume 1% of their body weight within that short period of time, whereas horses don't. So there is a definite difference in food intake. It would just be lovely to find the gene.

We're doing a bit of work here at Edinburgh, trying to first find a population that we can work in. Where there are so many factors, and, and we've chosen Icelandic horses, and we've got the start of a, a study going on where we, we're surveying owners to see if we can see if in these horses we can find a phenotype which distinguishes, obese from lean. And interestingly, 72% reported that their horses were highly motivated by food.

So it might not be a distinguishing feature, but it's an interesting way to go. And as I said, genetics and environments. So you can have the genetics of a Shetland if you live on Shetland, and you can eat whatever you like, and if you're exposed to snow conditions, then that's fine.

But if you're a Shetland pony who doesn't live that way and lives on lots of grass and is, stable during winter and fed even more, then you don't respond to those changing seasons, and, and that's where obesity occurs. So adipose tissue in obesity, we talk about obesity all the time, we don't often talk about the actual organ that is affected and that is our adipose tissue. Adipose tissue is essential for life.

So people with lipodystrophies, where they can't lay down, adipose tissue are very, very sick. So it shouldn't be demonised, and it's an amazing organ. It has a huge blood supply, and, a lot of intricate, immune, mechanisms going on.

And it's a major source of, of many hormones, particularly glucocorticoids, and it's responsive to insulin. And it's, it's where we store our energy, and we absolutely need that. And horses absolutely need to store that energy.

It's just what happens when you're storing too much. So in healthy in humans, when adipose tissue expands in a healthy manner, so you're in a slight calorie excess, maybe for a short period of time, you put on some fat, and that is in the, the guise of more adipocytes. So more fat cells, and they're all healthy and they maintain their blood supply.

If you tip over onto the chronic calorie excess, and, it's, it goes on for a long time, then you start to get unhealthy expansion of adipocytes. So instead of, getting hyperplasia, so more cells, you get hypertrophy, so that means bigger cells, massive cells, just to take up all this lipid. And the trouble is, the bigger the cell, the further it is away from its mitochondria, further the further all the energy has to go, and the larger the blood supply it needs.

And it starts to, it starts to die essentially when you get really, really obese, you get necrotic. Areas in the adipose tissue, and that sets up a chronic inflammation and cells that hypertrophy, so they get really, really big, are really unhealthy. They're under a lot of stress, and in adipose tissue, this results in glucocorticoid dysregulation, inflammation and insulin resistance.

So, that's what happens in humans. In horses, we've shown the same thing. This is, a paper that we published, I think last year or the year before, year before, and we showed that lean, horses have, lots of smaller dippocytes.

And obese horses have these huge dipper sides, and I promise you this is the same magnification. I was convinced otherwise for a long time, but I've, I've done it myself. It's the same magnification, so we've got these large unhealthy adipocytes.

And the adipose tissue starts to outstrip its blood supply and become inflamed, and it resists the effects of insulin. I think this is an important picture to remember and to try and communicate to owners that this isn't just like, oh, he's cute and fat. He's actually got a really unhealthy cells in that adipose depot.

So there's lots of talk in humans about the dangerous fat, and in humans, it tends to be the visceral fats and the fat around your belly. But, and in horses, everybody says it's the neck crest fat. But as I said earlier, neck crest fat actually doesn't look like fat.

So this is what adipose tissue looks like, these two slides that I've shown you before. This is healthy and this is unhealthy. And this is what neck crest looks like.

So it's hardly any actual adipocytes, and it's all fibrous tissue. And this is we stained with icosa red for the fibrous tissue, and that's what we see. Now, that's not to say it's not contributing, to the whole body instantin dysregulation.

And it's not, and it's probably the harm it's doing is not allowing for more lipid storage. So you get ectopic lipid, but it's not proper adipose tissue. And it's probably dangerous, but it's probably not as dangerous as visceral adiposed to shoot in horses.

So in obesity, it's all about balance. If you have healthy adipocytes, then, you are in balance in terms of your insulin and your glucocorticoids. But as soon as you tip unhealthy, large adipocytes, which are, out outstripping their blood supply, you get an increase in insulin cortisol, and that's where the cycle of, insulin regulation and hormonal imbalance starts in equine metabolic syndrome.

So insulin, just a quick recap. I'm sure you all remember this from, vet school, but, insulin controls the blood glucose. So you ingest carbohydrates, and the, and the initial, phase is the Einsular axis, kicks in with GLP one stimulating the absorption of glucose from the gut.

And then once it gets into the blood, you get stimulation from glucose from the glucose itself and from the GLP of the pancreas to secrete insulin. And that activates glut4 receptors in the insulin sensitive tissue, which is mainly the skeletal muscle, but also the liver and the adipose tissue. And, and these tissues take up the, the glucose, through the glut4 receptors, and the blood glucose level falls back down to normal.

Oh. But insulin also reflects blood vessels, and we'll talk about that a little bit later. So that's the normal, healthy way.

Insulin should act on skeletal muscle, liver, and adipose, and the glucose should get taken up. And then as the blood glucose falls back down to normal, insulin falls again to a normal level. Now there's lots of debate about what insulin resistance is and what insultant dysregulation is, and there's a huge amount of research going on in humans as to defining these and what the, what the actual process of events is.

Nobody can tell anybody for certain what happens as you get obese, why you become insulin dysregulated. And I think it's important to remember that there's probably a spectrum and that insulin dysregulation is not a homogeneous condition. People and horses can be affected in different ways.

So classic insulin re resistance is caused by possibly downregulation of insulin receptor or an exhaustion or resistance of those glute 4 receptors, which, to insulin signalling. So those are the ones that go to the cell membrane to allow the glucose in. And if you're resistant to insulin, then the pancreas keeps thinking you need more insulin.

And so you get a hyperinsulin anaemia until eventually the pancreas, the pancreas exhausts and you get type 2 diabetes, which we don't see often in horses. Probably because they don't live long enough. It's in dysregulation is just an all-encompassing term to include insulin resistance, but also to include the state where you have a hyperinsillemia is a primary cause and that and this causes insulin resistance over time.

And why does the hypoxemia occur? Well, possibly due to the dysfunction of the enteroinsular axis, so maybe increased capacity to absorb glucose from the gut. So that's your postprandial spike in insulin.

What we know is that incident dysregulation is caused by many things, but chronic inflammation that you see in, obesity, oxidative stress that you see in obesity, cortisol dysregulation that you see in obesity, GLP dysregulation, so gastrointestinal hormones, an abnormal lipidome and ectopic lipid accumulation. So lipid in your skeletal muscle, lipid in your heart, lipid in, In the liver, all of those contribute to insulin dysregulation, whether it's insulin resistance or it's post-ranial insulin dysregulation. So when I'm talking to owners, I try and tell them about the three types of insulin dysregulation.

It doesn't always go well, but, this is to explain the tests that I want to do to their horse. So I say, right, well, you can have, you can be constantly hyper insulin anemics. You're just constantly pumping out, .

insulin from the pancreas, and that's probably because you've got whole body insulin resistance, but not necessarily. It could be due to the absorption from the gut. But if you have that, we don't really need to do any other tests, because I know that high basal insulin, it is associated with insultant dysregulation.

It is insulin dysregulation. So that's the first test I always do is a basal insulin. And then the second test maybe is a postprandial increase in insulin test.

So that would be an oral glucose test or an oral sugar test. And then I also do a whole body insulin test. So that's a combined glucose insulin tolerance test.

And ideally, in all of my horses, I do all three. I probably tend to go more for a CGIT than an oral, but, that's personal preference. And if you have questions about that, we can talk about it at the end.

But But I think it's really important to remember that it's not a homogeneous condition. So if you do an oral glucose test, and it's normal, that doesn't mean to say the horse hasn't got instant resistance. It might just be that it doesn't have a postprandial increase in insulin.

So always hedge your bets and never test anything that you don't know what you're gonna do with the answer. So just very quickly about the equine pancreas, which nobody ever seems to ever talk about, but, this is some work that we're doing at the moment. So it's not yet published.

So, this is kind of a first look, but I thought I'd show you some slides. So we've got, just H&E staining of a healthy horse on the left, and a, a horse with metabolic syndrome on the right, and it's got, it had a really high insulin. And it looks like, we've done about 8 horses now, so sorry, about 12 horses, about 6 in each group.

And we can see that you get an increase, an apparent increase in islet number, on in metabolic syndrome. And just looking at the pancreas, they are friable. The tissue just crumbles when you deal with it.

The size of the islets are really variable. And there's increased blood everywhere. So there's congestion in all of the pancreas.

So even though the horse is able to produce a lot of insulin, the pancreas is in distress, is how I would, how I would describe it. Now in humans, islet associated, amylin polypeptide, is, or amylin is, thought to be the main reason that the pancreas starts to exhaust and stop producing, insulin and result in type 2 diabetes. It's a major secretory protein and it inhibits insulin and glucagon.

And yeah, in humans, monkeys and cats, it's associated with, with beta cell failure. So we stained for it to see if this is why, horses don't get beta cell failure because they don't have amylin, and they don't, they don't produce amylin, so. The top, the top three slides are a mouse, a healthy horse, and an equal metabolic syndrome horse eyelet, all stained for amelin, and you can see the brown staining in the mouse is amylin.

And also in Congo red staining, which is the bright, the bright white you see in this mouse islet, you don't see in the horse islets at all. So they don't appear to produce amylin, which might well be protecting them, from pancreatic failure. But what I would say is the pancreas is definitely not healthy.

OK, that was a little sideways move into, into the pancreas. Back to insulin. One thing I really like to tell my owners all the time is about the cyclicity of insulin and how it should change with season.

In horses. So they should become a little bit fat in in summer, not very fat, but they should become a little bit fat in summer, and they can cope with that. They get a little bit insulin resistant.

They're fine, because in winter, they lose all that weight and can become really quite lean, and that re-establishes their insulin sensitivity. But what we do obviously is we keep feeding them and that's why you get this cycle every year on year that they get fatter and fatter and more and more insulin resistant. So I think that's a really important concept to get across to owners.

And I really encourage them to, to use winter, take the rugs off, put the pony out in the field, use winter as your biggest friend in weight loss. And, and really treatment, I'm not gonna dwell on this too much, but treatment is reducing calories in and increasing calories out. So there's lots of, work at the moment going on on grazing systems, which will be quite interesting to follow.

We've just published this paper on, using straw, using 50% straw and hay mix to induce weight loss over winter. So, this was a group of horses that Red. Horse sanctuary, who normally would gain weight every winter because, they were supplemented with forage.

And so they were just standing in one place for a start. And they were eating a lot of forage. And it was getting worse each year.

So we, intervened, and gave one group of them 50% hay and 50% straw, and got a really nice, weight loss from every single horse. . And no episodes of, of laminitis in that group.

And it's something to think about. I, I, I don't think that straw causes any, any issues, unless you really don't have any teeth. So the horse is really old, maybe.

. I won't, I won't go off on a tangent about strip grazing. I'm not a big fan. I think it causes fast and famine.

And in fact, what I prefer is this huge field with really rubbish grass on it. That is much, much better than a small strip with lots on it, and then the horse stands next to the fence, staring at the new grass. And Getting very stressed because stress is never good, if you, want to protect your horse from laminitis.

This is just one little trick that we use if the horse is stabled. Putting the hay net in the middle of the stable. Not all the time, but over some periods can keep them really entertained for ages because it winds them up because they, they can't, they, they can't pin it to the, to the wall and just eat all the hay at once.

So that, that's quite a good trick. And increasing calories burns, in, in various, interesting ways. I think the use of trackways is gonna become really popular, and I really like it.

It encourages horses to move to get resources. So if you put water at one side of the field and introduce a trackway, then you'll encourages encourage horses to move. But there isn't really any evidence that, exercise per se can induce weight loss, but it can certainly aid weight loss.

And then what all owners want is a pharmacological treatment. I have to say, I very rarely prescribe anything other than, diet and exercise. In great detail.

I just, I prescribe them, but I rarely prescribe drugs. So the most classic one is metformin. Metformin achieves glycaemic modulation by, it targets both the liver and the intestine.

We don't really know how it works for a drug that is used a lot in humans, there's a very little evidence about how it actually works. And in horses there's huge variability on how they respond and that's probably because they might not have the receptors. Levothyroxine, I don't mind being controversial.

I don't think any vet should be using levothyroxine. This is thyroid hormone, it just increases metabolic rate. It induces short term weight loss, but also causes significant I would argue, psychological stress for the horse, they are wired to the moon, just like a cat with hyperthyroid, and I think it, it will eventually lead to horses having cardiomyopathy, but that just hasn't been shown yet.

Things to watch on the coming onto the market. I think the first thing that's gonna come onto the market soon will be in SGLT inhibitor of the glylazine family. They block renal reabsorption of glucose.

So basically you start peeing. Peeing the glucose out and there's been a couple of recent trials in horses and they did alter the, the hyperinmic response. So they're definitely one to watch, they'll be coming onto the market pretty soon.

. GLP inhibitors, GLP one inhibitors, we talked about those a little bit, well we talked about GLP a little bit earlier, that's targeting that post randial insulin response so inhibiting, inhibiting that glucose absorption from the gut. And there's also sweet taste receptor inhibitors which, So it's they're not actually in in the mouth, they're in the intestinal epithelium and they act with GLP to induce glucose absorption. That that's what the sweet taste receptors do, so inhibitors will stop that as well.

So that's just things to watch out for. Right. That was a rattle through equal metabolic syndrome and it's dysregulation.

And now a very quick rattle through pituitary pars intermediary dysfunction. A disease of ageing, as we know, very similar to Parkinson's Parkinson's disease in humans. It's a loss of dopaminergic inhibitions, the pars intermedia, and you either get hyperplasia or, an actual adenoma.

And the pars intermedia produces, ACTH beta endorphin clip, which stimulates instant release and alpha MSH. And the thing we measure is ACTH, but that's not to say that there isn't all of these, going around the horse's body when they have, Cushing's disease or people. PID.

And all, all these hormones do, the POMC hormones, they're called. All they do is prepare the horse for winter. So the ACTH stimulates steroid production, which, contributes to laying down fat.

Beta endorphin is a natural opioid, so it, it helps with. Stressful events and, and helps calm the horses down. Clips stimulates insulin release, which you need, if, you're going to, get as much glucose into your muscles as possible.

And Alpha MSH deals with skin pigmentation and hair coats. So all of them are preparing the horse for winter. So the way I describe it to owners is that a horse with Cushing's disease is constantly ready for winter.

They've got fat laid down, they may be a bit spacey, and they've got a long, curly coat. The only thing I'd say on this slide, this, it's a bit, it's a bit much, but, don't forget the pars to stylist. So the main source of ACTH in the horse is not the pars intermediia, it's the corticotropes in the pars de stylus.

And then ACTH response is a perfectly normal and necessary response to a stressor. So if you do not have any clinical signs in a horse at all. And you've had to chase it round the field in order to get a blood sample from it, then just think, could that elevated ACTH that you then measure be coming from the past to stylus as a normal stress response, be very, very aware of interpreting ACTH because we can't distinguish where it comes from in terms of parts to stylus or pars intermediate.

So this is just a picture of, some of the tumours that we see in the scoring system we have for the tumours in the pituitary. And then some work that we did on glucocorticoid receptor in the pituitary. So the pituitary, the pars intermediate has got glucocorticoid receptor, It does respond to negative feedback, and that doesn't seem to be different, in horses with PPID.

So it's not related to negative feedback. So the paradox of PPID particularly for somebody who works on steroid hormones, is that high ACTH should should stimulate your adrenal glands and get you to produce cortisol. But in these horses, we have a high ACTH.

We have all the symptoms of cortisol excess, which is why it was originally called Cushing's, but normal, so-called normal plasma levels. Cortisol levels. So there's been a, lots of discussion over the years, whether the ACH is just inactive, but I don't, I personally don't think that's true because you've got symptoms of glucocorticoid excess, you've got fat redistribution, you've got insulin dysregulation.

So, in our recent paper we showed that you had hugely increased clearance of cortisol, from, horses with PPID, so it's 40 and healthy and 150 in PPID horses. So that means the ACTH is active because the cortisol's coming from somewhere. And we also showed that androgen metabolites were up, so that's testosterone metabolites.

And that indicates that the adrenal gland is being stimulated. So I would argue that it is a syndrome of cortisol excess. It's just that we're not measuring it in the plasma because horses can clear cortisol so quickly.

But that doesn't mean to say we haven't got high levels in the tissues. So why do some horses with people I get laminitis and some don't? Well, it's all down to insulin, generally, and a little bit of adiposity.

So we showed that basal insulin was strongly associated with laminitis, as was Neckquest score. And if you give, a healthy horse insulin over an infusion, you get laminitis. So it makes sense that, that that's what's happening.

What we don't know is the link, and I'll talk about that a little bit later as well. So now we're gonna skip from PPID, the pathophysiology of PPID to a bit about cortisol, which isn't always covered in our CPD, so I hope you'll find it interesting. So cortisol is about coping with stress, it's about coping with long term stress and short term stress.

So, if you're a wild profalski horse and you get chased by a bear, which probably isn't this one, because it looks like it's in captivity, then your adrenaline kicks in initially to allow you to run away. But then as you have to keep running, your cortisol has to kick in to help your adrenaline. These days there's very little stress like this for horses.

Instead, we have more nutritional stress, so that is either lack of food or too much food. Both of those are in nutritional stress because cortisol is essentially trying to manage your glucose levels. It coordinates the short and long term response to stress and it affects how nutrients are used and how fat is deposited.

So you can imagine every time glucose is ingested, cortisol responds to allow you to manage where that where that glucose goes. If you've got so much glucose all the time because you're eating so much, it's very difficult for cortisol, to keep up and you produce more and more of it, and it counters the effect of insulin. It also has profound effects on blood vessels.

So the metabolic effect of glucocorticoids, this is good to know in terms of when you're giving steroids like dexamethasone and and prednisolone as well. It essentially increases, glucose. So it's, it's trying to protect the glucose levels in the blood.

So it increases gluco neogenesis and stops it being taken up by the muscles. And it also breaks down muscles in order to get more source of amino acids to make more glucose. So it's all about protecting the brain and making sure the brain has enough glucose.

So it impairs the increasing effect, which is the GLP one effect. So, it, it stops that effect on insulin. It recruit, it impairs the capillary recruitment, and it stimulates lipolysis in general.

It also stimulates lipogenesis when it's out of whack or in particular depots of fat. But in general, it's trying to maintain the blood glucose levels. And I won't dwell on this too much, but it's controlled at a huge number of levels, not just the HPA axis, which we'll learn about a vet school, but then in every single tissue in the body, there are fine tuning mechanisms to determine whether the glucocorticoid receptor and the mineralla corticoid receptor are activated by the glucocorticoid.

So that includes CBG binding and plasma. So how much cortisol is free to diffuse in. But also, transporters which transport cortisol out, and enzymes such as 11B to HSC1 and 2 which inactivate or activate cortisol in particular tissues.

And we can't live without plasma glucocorticoids, and we have two primary ones, cortisol and corticosterone. In horses, cortisol is dominant. In most rodents and bird birds, corticosterone is dominant.

And in rabbits, they're very clever. They have both in equal measure and depending on how stressed they are, they will produce a cortisol response or a corticosterone response. And glucocorticoid metabolism is very species specific.

Again, I won't dwell on this, but how you deal with your cortisol depends on what species you are. So a human goes down these pathways, the 5 alpha and beta THSs, whereas horses we found go down 20 metres of hydrocortisol. And what we find in, in fat horses is that clearance of glucocorticoids is increased.

So we've got a lot more to be dihydrocortisol in the urine, but also in the plasma. So whilst you don't have a difference in the actual cortisol levels, we know that the tissues are working hard to clear it. And when we looked in humans actually at this horse metabolite, we found that they also have increased 20B to DHF DH cortisol in their urine.

So there's, there's a lot going on in your cortisol metabolism when you become obese. So what can glucocorticoids do? Well, this could be, about a 4 hour presentation all of its own, but just to highlight a few things, it can cause insulin industrial regulation if you have increased glucocorticoids and inflammation, and, vascular dysfunction.

So all of the things which are hallmarks of, equal metabolic syndrome and endocrinopathic laminitis. So now if we move to endocrinopathic laminitis, the question always for me is how do we get? We know that insulin dysregulation is pretty much the, the middle, between giving steroids, having Cushing's, having metabolic syndrome, and getting laminitis.

Insulin dysregulation is there in the middle, but what we don't know is how that causes laminitis. How on earth does it cause the destruction of the laminar tissue? So the destruction of the lament tissue is, is like a is is a stretching.

In, in a sick horse with inflammatory laminitis, we get a tearing and a very dramatic breakdown and lots of activation of neutrophils and MMPs . Which just destroy the tissue like it does any other tissue if you have sepsis. But in endocrinopathic laminitis we get a much more stretching and er an elongation and a hyperplasia.

And we get cell stress and epidermal activation. And there's very few neutrophils. There's a bit of sterile inflammation, but it's not an itis, really.

It's, it's unlike, so this at the bottom is this tearing in inflammatory laminitis. Imagine you're sick mare with metritis who falls through her feet. That's, that's what's going on in her lamini.

Whereas your fat pony with laminitis, you've got this stretching, and it's over time, and it's chronic, and it's often. And subclinical. So how does insulin result in this?

Well, there's lots of different theories and nobody has yet been proven right or wrong. Yeah, it, it was thought initially, right, well, the insulin must act directly on the lamina, lamellae, but they don't actually express insulin receptor. So now it's thought potentially insulin acts on the, insulin like, like growth factor receptor, which causes proliferation of the epidermal, Cells, and, there is, there's a nice, article here, by Martin Silence's group, which has described what they think might be going on.

But certainly endo endoplasmic reticulum stress, definitely, and our regulation of, of M talk and and and this is where they kind of think that, the, Sepsis and endocrine laminitis cross, because you have this activation of PI3 kinase by either inflammation IL-6 or activation of the IGF-1 receptor. This is still ongoing. We don't know if this is what's happening, and my suspicion is that it's a little bit more complicated, but it's probably a component.

The work I did looked on the vascular, functioning, in laminitis, which was pooh poohed a long time ago, as being rubbish. And I, I looked at it because we know that glucocorticoids, cause vasoconstriction. And I was looking at glucocorticoid regulation in, in the, hoof tissue, and I was looking at it in vessels.

And what I saw. Was that horses with endocrinopathic laminitis failed to have a relaxation of their blood vessels, in, in response to acetylcholine. So what we've got here is the open circle, one graph at the top.

That is horses learn chopathic laminitis. The normal horse is the dark black circles where you get this profound relaxation of the vessel, right? And we don't see that in horses learn.

Crenopathic laminitis. They aren't relaxing as much. And it's not just the laminally, the lamina vessels.

It's also the, vessels of the face. So we looked at remote vessels. So that's this one here, and we saw the same thing.

So it's, it's a, a systemic endothelial dysfunction. Acetylcholine responds to, is, is, acts on the endothelium. So when you have endothelium dysfunction, this is what you see.

So, it, it, this is probably a component of it as well. Whether it's the cause or an effect, I don't know. But insulin, we know causes vasoconstriction, cortisol causes vasoconstriction.

If you put the two together, they cause endothelial dysfunction. We know people with insulin dysregulation have endothelial. Dysfunction, that's what makes them more susceptible to a heart attack, to, you know, to carotid plaques.

So, it makes sense. I don't, I'm not saying it's the only thing, but, keep an eye out in terms of the literature and where it's going. It's definitely gonna, gonna be interesting in the next few years.

And then finally, could glucocorticoids act directly on the lamellae? Possibly, if we look at humans with Cushing's disease who have high cortisol levels, they get, this epidermal stria. So, the stretching of the skin, and it, so it could well affect the epidermis.

I don't think that glucocorticoids are necessarily high enough in the laminar tissue, but it's very difficult to quantify them. So that was a rattle through a huge amount of pathophysiology of the of endocrine disease and I hope it was of interest, and I'm happy to take any questions if there are any. Wow, Ruth, thank you very much.

That was, that was so informative with such a lot of information in there for everyone to, to be thinking about. So does anyone, if anyone has any questions, if you'd like to pop them into the question and answer box, we can then put them through to, we can put them over to Ruth. So, our little little ponies that end up with laminators they're always such a sad sorry sight, aren't they?

And you can see the owners do try so hard, most owners seem to be trying so hard to try and get some weight off them, and it just seems to be something that they just seem to keep coming back to and back to every time. Yeah, it's, it's not, yeah, gosh, it's, it's, it's such a tough condition, I think to, for, for everyone to be managing, bless them. So I think well I think you've answered absolutely everything.

Everyone was probably wanting to ask you, with, with such a lot of information in all of them slides. Did you say you're going to, you're sorting out some not handouts as well that you think should be available with the webinar that at some point. Oh yeah.

And if, yeah, and if anyone does have any questions, I see your, your email is on that last slide there. So if anyone does have any questions, that you can't think of at the moment. So yeah, Ruth, I think we, we can call it an evening for after this.

That was, I really, really enjoyed that. Thank you very, very much. So I would like to thank.

Thank the webinar vet for everything this evening and thank you Ruth for really, really informative talk, and thank you everyone else for attending this evening. So you take care. Thank you very much.