Thank you very much, Sophia, and I'm delighted to be here to talk to you guys today, about equine endocrine disease, and I'm gonna really try and focus on what's new, what's in the literature, what's going on in the research world. I think we all kind of are familiar with the basics now of, of, equine endocrine disease, but, it's a ever developing field, and, and it's quite exciting things going on, but there's still a lot we don't know, so hopefully you'll find it interesting so. We're gonna focus on the two main endocrine diseases that affect our, our domesticated horses, equine metabolic syndrome and pituitary powers intermediate dysfunction, so equine Cushing's disease.

And I'm going to really go through the pathophysiology, diagnostics and treatment of these, and, and try and, as I said, draw out the literature that's that's really relevant to us and to what we can tell our clients and how we can manage these horses and and how we can communicate better with our clients about these diseases. I, I could go on for hours, so, if I skip over things, I apologise, but please feel free to think of any questions and, and ask me at the end. So we're gonna start with equine metabolic syndrome.

Equimetabolic syndrome is defined as a collection of risk factors including obesity, insulin dysregulation, and genetic predisposition, which results in increased susceptibility to laminitis. So we've really stolen this definition from the human researchers, the human medics, who define human metabolic syndrome as a collection of risk factors including obesity, insin dysregulation, and genetic predisposition, which results. And increased susceptibility to cardiovascular disease and type 2 diabetes.

So we've completely stolen their definition, but we've supplemented cardiovascular disease and type 2 diabetes for laminitis, and I would argue that actually laminitis is a cardiovascular disease, but we can talk about that a bit later. So really we need to understand that it's a syndrome. It's not a disease per se.

It's a syndrome. You need to have these factors in order to, to have equine metabolic syndrome. So in the human, this is what metabolic syndrome looks like.

We've got that typical abdominal obesity, a person at high risk of a heart attack or a stroke, hence cardiovascular disease, and developing type 2 diabetes. And in our horses, this is what metabolic syndrome looks like. So we've got our typically obese, genetically predisposed Shetland pony, and you don't have to have laminitis to have metabolic syndrome, and I think that's really key to say that the holy grail, of, of diagnosing equine metabolic syndrome is to diagnose it before laminitis develops because sadly laminitis is what's going to be life limiting.

These animals being fat per se does not limit your life, but the morbidities associated with being fat limits your life. So we really need to try and get the laminitis susceptibility defined in these animals and be talking to owners before they've even developed susceptibility before they've even developed laminitis. So I'm going to split this now down into the different components that I've just talked about.

So we'll start with genetic predisposition. So what does genetic predisposition mean? Well, it just means that certain breeds or families or individuals or individuals in a certain environment are more at risk of developing the syndrome than others.

Now they may be at more risk of developing the syndrome overall, so this collection of risk factors, or they may be more susceptible to the individual components or contributing factors. So just like people, some horses may be more likely to get fat or more likely to be. Insulin resistant or I certainly I recognise it more likely to have a high appetite than others.

So some some horses will eat more than others. And so those individual components can then increase their risk of developing metabolic syndrome. It's really important to say that this does not mean That these individuals who might be more susceptible to either the syndrome or the individual factors are predestined to develop EMS.

They require environmental triggers as well. So horses in the wild, even native pony breeds in the wild, don't become insulin dysregulated necessarily, and that's not necessarily because they don't get obese, because if we look at wild horses. They will become very fat in the summer when there's loads of grass and loads of nutrition in the grass, but they maintain their insulin sensitivity by cycling this obesity, so they'll become skinny in the winter when there's no food, and then they'll put that weight back on in the summer.

Obviously in our domesticated animals, we feed them all year round, so we've abolished that cyclicity to the insulin sensitivity, and that's probably a key factor. In the development of, of equal metabolic syndrome. So if we split down these, different ways, you can be genetically susceptible.

Well, there's breed. We have a limited, definitive evidence of breed, predisposition, but we know that certain breeds. Are overrepresented in our studies.

So remember what we haven't done is take a native pony and a horse and keep them in exactly the same environment for a long period of time and see if the pony is more likely to get metabolic syndrome. We've just looked at which horses or ponies present with metabolic syndrome. So we all know that pony breeds, Morgans, American Standardbreds, Spanish mustangs, they're more likely to be in studies of metabolic syndrome.

But what these studies have done as well is include their lifestyle, I suppose. So a native pony breed is less likely to be a high performing athlete than, say, a thoroughbred. So that's not to say that if you don't stop, if you stop exercising a thoroughbred and you feed it enough, it probably will get equine metabolic syndrome in the end, but you'd probably have to feed it more for longer than you would the pony.

I hope that makes sense. So then that's within a breed, but within a breed, we also have individuals who are more susceptible than others. So we have an extra small pony herd here and some of them are much more susceptible to being fat and to getting insulin dysregulation and therefore metabolic syndrome than others.

And there's some really interesting work coming out of the states now looking at individual single polynucleus, single nucleotide polymorphisms, which are associated with your individual increased likelihood of getting metabolic syndrome. So this study here has found the FA 174A allele as as an increased risk of getting EMS. Unfortunately we don't know what this allele does.

We don't know what this gene does, which is, which is disappointing because it's not giving us a, a causative link there. But it does mean that you can tell your owners, you know, within, within a breed there will be individuals who are at a higher risk as well. And then we've got epigenetics.

So epigenetics is the alteration of your genome by environmental factors such as DNA methylation, and your genome is set on when you conceived, but it can be altered to a certain degree by lots of environmental factors such as maternal nutrition. Maternal stress or steroids and environmental factors such as endocrine disrupting molecules, things like that. So things that can influence your genome after you've been born or while you are in utero could be important, but the likelihood is really that equal metabolic syndrome is a multifactorial syndrome.

It's a combination of your genes plus your environment making you more susceptible to metabolic syndrome. So let's go through to obesity now. Obesity is increasingly a problem in domesticated species and particularly in the developed world.

And we define it as excess adipose tissue, and this can either be all over the body or in discrete areas. And, it's due to an imbalance of calorie intake versus expenditure. Eat too much, don't exercise enough.

So I've tried to pull out some prevalent studies from around the world. I know our audience is international, but really we're sitting at about 30% of domesticated horses and ponies are overweight or obese, and that's a pretty high, high level and increasingly we're seeing what the welfare implications are of this. And I just drew out this, .

Study from this, yeah, study from Sweden here which highlights their legislative requirements that horses should be fed so they do not become over or underweight. Classically, we've always looked at welfare of animals as as making sure they have enough food, but increasingly, we're, we're recognising obesity as a as a big welfare issue. So how do we recognise obesity?

Well, we can score obesity on two different scores, really. The best ones are the Caroline Huntington 1 out of 5, probably best for owners because it's a bit simpler, and then the Hennecker scale out of 9. But we need to recognise it as vets, obesity and owners need to recognise it as well because until we have the owners on board we can't, we can't tackle it.

So I drew out this study because I think this is a really interesting study, by. Caroline Argo's group at Liverpool, which show how many the percentage of owners that can recognise horses at different body condition scores. And we see here, so for example in Panel J, they have no difficulty recognising that this horse is fat.

98% know that it's got a body condition score of 9 out of 9. It's morbidly obese. But yet we have, if we look at panel K, where the horse is probably an ideal weight, we have a very low number of people who can, who can recognise that.

And I think this is going to be always the sticking problem with our owner compliance is getting them to recognise obesity in their own horse because it's so subjective sometimes and there's so many breed differences and we have no way of in measuring internal adipose tissue. I would advise you to have a look at the scoring of the neck crest system. That's quite useful, and neck crest adipose, the size of it has been specifically associated with laminlytic risk.

That's not to say the adipose tissue itself is bad, but it's probably more likely that we can readily measure net crest fat, and the more likely you are to, the more the fat you are, the more likely you are to have net crest fat. So how does adipose tissue contribute to the syndrome? Why are we telling our owners that it's bad for your horse to be fat?

Well, adipose is not an inert tissue. It's, I would argue it's the largest endocrine organ in the body. It secretes, metabolises, and alters multiple hormones and affects both the dipocytes and cells, and it releases these factors into the systemic system.

So, factors include leptin, which affects appetite and metabolic efficiency, adiponexin, which we'll talk a little bit about in, in the diagnosis section. It's an insulin sensitising adipoine. It has adipose is a major site of insulin signalling, and cortisol regulation.

And the key thing is that as your adipose tissue expands, it becomes unhealthy. It outstrips its blood supply, and if you outstrip a blood supply, you become unhealthy, the tissue starts to die and you get a pro-inflammatory response. And this, this adipose is unhealthy, so I'm going to show you a little bit of data which we've got, which is unpublished as of yet, but I thought was interesting.

So these are two sections of adipose tissue here. The one on the left is from horses who are healthy, body condition score, so around 2.5 out of 5, and this one here on the right is from a horse with a body condition score of 5 out of 5.

And I promise you these are they're taken at the same microscopic level and yet you can see that the horse with metabolic syndrome or obesity has huge adipocytes, really hypertrophic adipocytes, and unlike the horse with a healthy horse which has much smaller and a lot more adipocytes. So we know there's a fundamental change in the way your fat tissue looks when you're obese, and that's, that's not healthy. OK, so moving on, we'll talk about insulin.

So just to recap, insulin controls your blood sugar. So the horse will eat the grass, you get the sugars in the guts, the grass haven't been broken down, the sugars are absorbed into the bloodstream. Insulin is released from the pancreas and it causes uptake of that glucose into your tissues.

And the top insulin independent tissues in in all species are the muscle, liver, and adipose. And if we think about our horses, they have a huge amount of muscle. So, so in horses, that's probably the most important site for, for insulin action is the muscle, which is why horses can be exquisitely sensitive to insulin.

So athletes which have a high metabolic turnover in their muscle are very susceptible to insulin, and that's a good thing. So we want our tissues to react to insulin to be able to take up the glucose. But what happens in horses' metabolic syndrome is they become insulin dysregulated.

So it's probably frustrating that we keep changing the wording, but we no longer really just call it insulin resistance anymore, and that's because it, it, a horse can present with straightforward insulin resistance where the whole, all the tissues in the body stop responding to insulin and so the pancreas keeps producing more that's compensated insulin resistance. But equally there are horses that have a postprandial hyperinsulinemia, so after they've eaten, they have an exaggerated insulin response or they have a constantly high insulin level in the blood or only certain tissues are insulin resistant, so muscle maybe or adipose but not everything. So we've probably in most horses get a combination.

And that's not necessarily that important for you to understand, but what is important is that it affects what your diagnostic tests are telling you. So insulin resistance in its most basic form is described as the failure of tissues to respond to normal insulin. So you've got this insulin wanting to push your glucose into the tissues and the tissues just aren't responding.

And we don't know why that is. We think maybe you may have a reduced number of insulin receptors in these horses or a reduced affinity of the insulin receptors for insulin or a defect in the intracellular signalling following insulin and stimulation. It's incredibly complex, the whole, all the pathways of insulin.

So I won't go into it now, but needless to say that we don't understand enough and the horses tend to get compensated insulin resistance, so that's when the pancreas just keeps producing more insulin. and that's why we get high levels of insulin in our horses. Uncompensated insulin resistance is more common in humans where you get pancreatic exhaustion and the, and the pancreas can no longer produce insulin and you become insulin dependent.

But the key to say is whatever happened, insulin is having loads and loads of insulin or insulin dysregulation is really bad for you. If we infuse horses with insulin, whether they're horses or ponies, whether they're susceptible breeds or not, they will get laminitis if we give them enough. So that's, that's kind of the key to remember that insulin is great, you need it, it's essential.

You can't live without it, but too much of it is really bad. So why do you develop insulin resistance and dysregulation and, and it's so complicated and we don't really know in the horse, but lots of people are, are working on it. As I said earlier, the adipose tissue as it's expanding is becoming unhealthy.

And it basically goes into a pro-inflammatory response. So you have low grade chronic inflammation in your body as if you had a chronic infection when you are morbidly obese. You're producing cytokines just like you would in response to an infection, TNF alpha and IR1 beta, and this will affect your skeletal muscle metabolism and your response to insulin, both the adipose tissue and the muscles.

So it makes you less likely to respond to insulin in a chronic inflammatory state. The other factors that are coming out as important are gastrointestinal hormones, so glucose-dependent insulartrophic polypeptide, GIP promotes insulin secretion, and we can see in the graph down the bottom that people have shown that increasing body condition score increases GIP. An increasing cresting neck score increases GIP.

So it might be that as you become obese, you produce more GIP, which promotes insulin secretion and therefore, it, it, it increases the amount of insulin you have circulating and is more likely to make you insulin resistant. What I work on is cortisol and cortisol dysregulation in horses' metabolic syndrome. We know that cortisol classically antagonises the effect of insulin, and we know these horses don't have, High levels of circulating the cortisol necessarily, but I'll show you a bit of data later showing that they definitely have tissue changes in their cortisol.

Other things that might be important, oxidative stress, so that, that's to do with the chronic inflammation as well. And then, actually building up lipid in your muscle, because you're so fat, the, the lipid can't go into the adipose anymore, it goes into the muscle tissue. And that, that can directly affect your ability of muscle to respond to insulin.

So there's loads of factors and, and we don't really understand all of them at the moment. So how might insulin or in instance regulation cause laminitis? Well, this for me is, is the holy grail of understanding.

We know that these horses are insulin regulation. We know if we infuse insulin, they get laminitis. So what's the missing link?

And this is theoretical and my opinions based on the literature that's coming out, but there are probably two main ways that insulin could result in laminitis. How does it affect the feet? Well, it could just affect the vasculature directly, and we know that that definitely happens in humans.

We know that humans with high insulin levels have stiffer vessels and more likely to get cardiovascular disease associated. Just with, with having insulin resistance. And so we could be inhibiting the blood supply or at least changing the blood supply to the hoof.

And the endothelial cells are likely to be key in that. And we know that a lot of these horses with metabolic syndrome have systemic hypertension, so that could also be in factor. And then we could have direct effects of the insulin on the actual laminar tissue.

So rather than a systemic effect, we've got a direct effect on, on, on the laminar tissue. This could be via insulin-like growth factor causing epidermal stress. So the actual tissue in the laminatis in the lamina is affected or causing oxidative stress of these tissues or changing glucose availability or insulin could it could cause protein metabolism.

There's not a huge amount of evidence for that. But certainly I've got some evidence that the insulin, high insulin levels, initiate a cortisol dysregulation of these tissues which could then cause them stress or directly damage them. So just to pick out one of those, these are some data that I published last year, or 2016, sorry, showing that horses with endocrinopathic laminitis, so these are horses with either metabolic syndrome or Cushing's disease, and they have endothelial dysfunction.

So this is a test where we took their vessels out of their feet and we looked to see how they dilate. In response to acetylcholine, the classic vasodilator, and, and this is the, this is what the horse should do this so the full circle, the dark circle, the black circles is showing the dilation on, on the left. This is what they should do, and the horses with the open circles here show the laminitic horses.

They just don't dilate as much. They do not respond to acetylcholine as well. And so they have an endothelial dysfunction.

And interestingly, this was not just the vessels of the feet because we also took vessels from the the facial skin and the same effect was seen. So it's a systemic effect. And we're doing more work on this now to work out what's going on and maybe try and interrupt it and and develop some therapeutics.

So what else is going on in that metabolic syndrome? I always think it's important to talk to owners about, OK, well, they might get laminitis and that will, will definitely be life limiting. But also there are lots of other things going on.

If you went to your doctor and you were morbidly obese, they would talk to you about all of the possible things that could be happening in your body which are not good. So there is, there's quite a nice bit of research coming out now about, about what happens to the heart, . In, in metabolic syndrome, and we know that that you can get myocardial hypertrophy.

And we don't think that these horses are going to be more susceptible to heart disease, but it may certainly affect exercise tolerance, and, and again, it's affecting their blood flow, so it might affect the blood flow to the feet. We know that they have abnormal lipid metabolism, and abnormal lippidone. We can see in this graph in the corner here, they have a strange lippidome.

Reproductive function is going to be affected, and if these horses are breeding or you've got a pony stud, you know, you're going to need to talk to about, talk to these owners about that. Insultant resistance causes subfertility certainly in humans, and I've got some data showing that horses with females with equine metabolic syndrome have increased urinary androgens similar to polycystic ovary syndrome in humans. So and there, there seems to be an association with metabolic syndrome and a failure to enter any stress.

We don't know about the effects of pregnancy and gestation. We can only kind of, speculate about those, but it's certainly worth talking to your clients about. And what I work on is cortisol dysregulation, and I found this is the data I published in Nature Scientific Reports last year showing that horses are special when it comes to glucocorticoids.

They metabolise cortisol through a particular route called 20B to dihydrocortisol. You don't need to know all this, but what I found was that horses have, they don't have change in cortisol levels, but they have a change in this metabolite, 20 beta dihydrocortisol in their plasma and in their urine. And I've gone on to show that this is an active metabolite.

This can act on the glucocorticoid and mineella corticoid receptors. So there's quite a lot going on in these horses that we don't understand. Take a message.

We don't understand enough, and keep on top of the research because there's lots going on at the moment and try not to get frustrated that we are constantly changing names and that's just as we develop our understanding of the pathophysiology. So moving on a little bit more practical now, we will talk about diagnosis of, of equine metabolic syndrome. So the best place really to start is, is doing a fasting glucose.

So I said that a lot of these horses will have a basal hyperinsulinemia, they'll have high insulin just on a resting sample, and we tend to do a fasting insulin and there's much debate as to what fasting really means. Does it mean just no supplementary hard feed or does it mean no food at all for 6 hours? Does it mean soaked hay?

My, my understanding and what I do is I wouldn't allow them to have grass or supplementary feed to any hard concentrate. I would tend to starve them overnight, so give them their last hay net at night, and then don't give them anything in the morning before you test. But if the horse is getting very stressed, or agitated, then I think you can perfectly acceptably give them soaked hay.

But you need to write down what you've done because next time you test them to check how they're doing, you need to be able to say, this is what I did last time. I gave them soaked hay, you must give them soaked hay the next time. So consistency is really the key when measuring fasting basal insulin.

Don't get too hung up about, about what you've actually, how you've actually fasted the animal, but, but be consistent in how you do it each time. Do you need a serum sample? There's a cutoff that's been validated on 3 essays of, of 20 microinternational units per mL, and that, that doesn't necessarily matter.

It doesn't matter necessarily which . Met your lab is using to test the insulin, but it's important to know that you use the same one each time on the same horse. So try not to send to different labs between horses within the same horse.

So if you're testing, just make sure you send to the same lab so that you're using the same assay because that can be slightly different. You can store the blood at room temperature, for, for a while and have no effect on measurements, so that's quite great. That's great if we're out out and about, during the day.

Don't be concerned about taking a blood sample and then not getting it back to the practise till the end of the day. Warn owners about false negatives. It, it's, they're very, very common and, and that's just because not all horses have high circulating insulin levels all the time.

That doesn't mean to say they're not insulin dysregulated. If, if they are, if it is high, great, we've gotten in and just regulated horses fantastic. If it's not high, then I would counsel your owners that you may need to do some more dynamic testing afterwards, to work out exactly what's going on.

I, I see as a clinical impression that cobs are particularly likely to be a false negative on their, fasted basal insulin, and, and that often need dynamic testing, but as I say, that's a, that's an anecdotal observation and, and one I'd be interested to know if, if other people see. And proxies, so the, the risky score and the MEG score are measures of insulin sensitivity that you might see written about in the literature, they're only as good as the, the basal insulin that you've, you've measured, so I wouldn't be worried too much about that, but you might see that in the literature if you, if you come across it, and it, it's basically from human calculations of, of your pancreas, pancreas ability to secrete insulin and your tissue's ability to respond, but it doesn't really give you a huge advantage over just your fasting insulin. So if you want to do some more dynamic testing, they're more sensitive than basal testing, but you need to know what you're testing.

So remember we talked about the horses can have a postprandial response to glucose, or they can have whole body insulin resistance or they can have both. And, it, I, I understand why people are choosing different tests, but, and that's fine. There are lots of different tests out there, but you just need to know what you're testing.

So if your test, so if you do an oral sugar test or an oral glucose or an in-feed glucose test, you're testing the postprandial insulin response to glucose and it may well be exaggerated. But again, beware, it may not be exaggerated because that may not be how the horse's insulin is regulated. And I know I'm muddying the waters here and making it complicated and, and it's not, it's just about knowing exactly what you're testing.

So if you want to test whole body insulin sensitivity, then I'd advise a combined glucose insulin tolerance test. And I would argue that that's, it's as easy as doing an oral glucose test. it, but it's, and in the ideal world, you would do all of them.

You do fasting insulin, you would do, an oral glucose test, and you do a combined glucose insulin tolerance test. The FSIGTT is a frequent sampling insulin glucose tolerance test. It's mainly used for research.

It's quite labour intensive. I wouldn't advise it in the field. So the oral glucose test, you fast the horse overnight.

Again, I think that's quite important to define how you have defined fasting, and then you sample for glucose and insulin at T0. So before you give any insulin, sorry, before you give any glucose, I think that's really, really important and quite a few people miss that stage out, but really you're looking at the postprandial response. And so if you didn't know what it was in the first place, it's very difficult to assess the response, as it were.

Then you give glucose and powder in the chaff and you sample for glucose 2 hours later. And normally the insulin concentration is less than 180 microinternation units per mL at 2 hours. The variability introduced in this test comes from the fact that you have to make the horse eat it.

Now, ponies are usually fine because they'll eat anything, but you're giving them quite a lot of glucose, so it doesn't taste very nice to them that, you know, they've not technically got a sweet tooth, so that, that may introduce some variability and gastric emptying as well. You're relying on on the horse gastric emptying at the same time for all horses and the significant breed variation. But it's a test of of postprandial insulin response and it's perfectly valid.

The combined insulin tolerance test involves you fast overnight again, place a little short stay catheter in, test the insulin glucose at T0 as you would for the oral glucose test, and then you give glucose IV followed immediately by insulin IV, and then you sample up to about 45 minutes. And the horse should have responded by 45 minutes by dropping its glucose, so it has an initial peak because you give it glucose, so it's glucose level shoots up. And then it should come very rapidly down because the incident is acting really fast to remove that glucose from the system and take it up into the tissues.

So the glucose should be back to normal or below what it started at by 45 minutes. And if it's not, then the horse is insulin resistant. So it's not really any longer than testing the horse for an MV test and then, and then testing again two hours later.

It just involves putting an intravenous catheter in. So I'd encourage you if you've got difficult cases or you've got owners that are willing and and and on board with testing to to try a glucose insulin tolerance test. And you can also measure the insulin at times so you could take another blood sample at 45 minutes to measure the insulin and you'll see a post glucose response to insulin that is, that is very abnormal.

This horse ironically was called Biscuit, who had, who was very insulin resistant. OK, other tests, well, we can do haematology and biochemistry, but they're rarely altered unless there's other pathology going on, but it may be worth testing. Triglycerides may be high, and you would be concerned about that in terms of hyperlipidemia and hyperlipemia, which we don't have time to talk about today.

But remember that actually there's probably more subtle changes in lipid metabolism that we wouldn't find out unless we did the Lipidone. A new test being offered is a high weight, high molecular weight adiponectin. I said earlier that adiponectin is the insulin sensitising hormone, and a low adiponectin has been associated with obesity and laminitic risk.

It can be measured by radioimmunoassay or elizer. But at the moment, I'm sitting on the fence as to whether it offers an advantage over just an insulin or a dynamic insulin test in terms of laminitic risk. I'm not sure, there's a huge advantage because remember, all of these tests, what we're testing is laminitic risk.

We're saying, yes, your horse is insulin is regulated and therefore it's more likely to get laminitis. And if it has a high consistently high insulin level in its blood, it's much more likely to get laminitis because we know that if you infuse them insulin, they get laminitis. I'm not sure adiponectin yet offers a huge advantage over insulin, but if the owners are on board and I'm wanting to do all the tests, then I would definitely test it.

Leptin might come out as being important soon. It's not currently commercially available, but it, it would be important. Horses tend to have a high leptin level when they've got metabolic syndrome.

And GLP that we talked about earlier, the results aren't great yet, and, and it's quite a difficult hormone to measure, so keep your eye out. That might be one that, that comes onto the market. So the take home message from that is diagnosing its resistance helps us insulin dysregulation helps us predict laminitic risk, and, and that is why you're measuring it.

If the owners are like, why, why do we have to measure insulin? Well, you don't. You could just say this horse is fat and it, and it's a pony, therefore, it's got 2 out of the three risk factors for, for being a metabolic syndrome candidate.

But, if you know exactly what its insulin is doing, then you know how likely it is to get amminiitis or not. So treatment, treatment is not rocket science. Diet plus exercise equals weight loss and better insulin sensitivity.

We need to get these horses moving and we need to stop feeding them. So, a key, I, I've made that sound a bit glib and I, I've kind of been a bit flippant about that, and I know that in practise it is easier said than done. So we did this work when I, in, in conjunction with the University of Liverpool, looking at, could we, induce, an, an improvement in insulin, through case horses managed at home by their owners.

And we managed it. You can do it, but the key thing for us, the key finding in that study was we needed to personalise the modifications. We couldn't just say, you know, you need to feed your horse less and exercise it more.

We have to give very, very specific instructions. This is exactly what you have to feed this horse. This is how much you have to exercise it.

You know, we did a bespoke plan for each horse, and that is going to be key. And we know. That that a clinical nutrition counselling, really helps.

It helps in human weight loss. It has to be modified for you and that's how you get compliance and, and if you take home nothing else from that, I'd, I, from this lecture I'd say that's the most important thing really take the time to, to develop a plan with your client so your client is on board. I thought this was quite an interesting study from America showing what owners used as their management strategies for instance this regulation.

So they know, they know that a low carb diet and exercise is important, but it's just and soaking hay is up there and encouraging weight loss. So, so they know, and it's just a matter of helping them achieve those aims. And understanding what a low carb diet is and what exercise means, you know, to increase a horse's heart rate, you need to be trotting quite fast.

Walking around the paddock does not increase their heart rate. And this was just I thought was quite interesting that that quite a few people got additional information from farriers and family members are over and above their vets. So it's important to, to inform all of the community.

Dirt modification, just a few tips. Soaking hay is, is always really good. Obviously, it significantly reduces the sugar content and accelerates weight loss.

But beware of, your dry matter calculations, make sure you calculate your dry matter post-s soaking. Now, question owners always ask, oh, but if I don't give them enough food, they eat their shavings and a nice little study that came out of Liverpool say yes, they do eat their shavings and about 50% of them on a restricted diet ate shavings, but actually it was a negligible amount and it didn't do them any harm. So that's something to tell your owners if you're, if they're very concerned about it.

The other thing that I am a big fan of is grazing mud muzzle. They reduce intake. It takes about one week for the horse to adapt.

It may take longer for the owner to adapt. They often are more stressed by it than the horse. But using a grazing muzzle can significantly reduce intake and allows them still to have that stimulation of grazing, which is important.

And you can double hay net or hang the hay net in the middle of the, in the middle of the stable so that it's more difficult for them to get. And I wouldn't say to completely eliminate pasture because grass is not always the enemy. If you can get these horses insulin sensitive and you can put them on poor pasture, then they can live a perfectly normal horse life.

Exercise modification just to say exercise alone is not enough, and there are some interesting studies out there of some more, unusual methods of, of doing exercise modification horses. So Belli Atta published some nice stuff on, on, on. Swimming and horses, and this is a design of a dynamic feeder to make the horse work for its food a bit more as much as you see in in management of cattle, they, they had to open the door in order to get the hay rack and, and that helped a little bit and I think it's quite an interesting thing to look at.

So we have drugs. I won't dwell on these, but metformin is often used. Nobody knows how it works, which is terrifying.

We don't even know in humans, and they use it quite a lot in humans, but never as a sole therapy in humans. It's always an adjunct. It's got poor bioavailability in horses.

You will get some that respond and some that don't. I wouldn't put all your eggs in the metformin basket is how I'd say it. If you're desperate then try it, but I don't think it's going to be .

The wonder drug and there are some other things and there's some new research on the spirulina and microalgae so keep an eye out for, for new treatments that are are coming on the, on the market or certainly coming into the interesting literature. But really, the take home message is client compliance is key and weight loss is induced by management changes and, and not really by drugs. OK, so that was a whistle stop tour of some, some factors about equal metabolic syndrome.

I realised I haven't covered all of them, but I'm going to move now on to pituitary paths intermediate dysfunction, and we're going to review the pathophysiology, look at the association between PPID and laminitis and reviews and the diagnostic testing and treatment. I spent a bit more time on equal metabolic syndrome, so we're happy to answer any questions at the end about PPID as well if I, if I don't cover everything you wanted to know. OK, so PPID equine Cushing syndrome, it's a disease of ageing, seen in horses over the age of 15, and it affects the pars intermediate of the pituitary.

So just to recap, the pituitary in the horse is made up of four sections. The past tuberalis, which is just a stalky. Which attaches it to the hypothalamus, the pas de stylus, which is the main source of your thyroid stimulating hormone, your, growth hormone, your ACTH, and, your gonadotrophic hormones and your prolactin.

The paths intermedia, which, is number 3 here on the, sorry, sorry, 2, I don't know if you can see my, little pointer, but number 1 is the past tualis, number 2 is the path to stylus. Number 3 is the pars intermedia, so it lies between the par nervosa, which is number 4, and the path to stylis number 2. The paths intermedia produces this very long peptide called the POMC peptide, a pro opium melanocorticotrophin peptide, which is cleaved into different things by the melanotropes in this section of the part of the pituitary, and it's cleaved into ACTH, beta endorphin, clip, and alpha MSH.

And then just to finish this diagram, number 4 is the pars nervosa, so that the posterior pituitary, which produces your vasopressin, your antidiuretic hormone, and your oxytocin. So in horses, for some reason, we seem to get tumours of the pituitary of the, sorry, the pars intermedia. Unlike in dogs where it's more common to get a positive stylist tumour, and in humans it's more common to get past the stylus tumour.

In fact, humans don't really have a pars intermediate. Their melanotropes are scattered through their paststylus. And really we understand that they Horses have a path into media because it's the the seasonal variation bit of the pituitary, so it prepares the horse for winter by producing ATH beta endorphin clip and alpha MSH, which will change the the horse's response to insulin and they redistribute fat and they increase hair and pigment.

And in PPID, we get a tumorous growth, in the pars intermediate, and it's probably due to a loss of dopamine inhibition. So the normal inhibiting, nerves to, to the pars intermedia is, is dopamine coming from the hypothalamus, and, we seem to lose those in PPID. And so if you stop inhibiting any sort of gland, it will just grow and grow and grow.

And that's what we get. So we get a hyperplasia and then an adenoma growth. So this is a really nice paper which is a scoring system of PPID in horses.

So this is a normal horse pituitary, and this is a horse with a massive pituitary treatment and we've got everything in between. So everything over about 3, you'll get clinical signs per se and increased ACTH and these drawings are really nice just to show how the pars intermedia grows and eventually gets massive. And you can see how it's squashing everything, it's squashing the positive stylist there.

And it's squashing the pars nervosa and so that's why, that's why you might get effects on drinking and, and urinating because it's affecting the production of vasopressin from the pars nervosa, the, posterior pituitary. So what clinical signs do we see? Well, we're preparing the horse for winter and we're in a constant preparatory state.

So we have a long curly coat, as, as I said, excessive drinking, urinating may be due to, due to squashing the posterior pituitary. We distribute fat all about the place. We've got high ACTH and so we've got lots of cortisol in our tissues, certainly I'll talk about that a bit later, but tissue, cortisol breaks down muscle and so we get muscle wastage along the top line.

And we get a saggy belly probably because of muscle wastage around the abdominal muscles. We can get recurrent infections, poor exercise intolerance, but really the life limiting effect of PPID is laminitis, and the horses that are going to get laminitis with PPD have insulin resistance. So about 50% of horses.

With, PPID, we'll get laminitis, and those are one, the ones with insulin dysregulation. So that's really important to know if your owners are asking you if it's gonna get laminitis or not, or if you see a PPID horse and you can't understand why it hasn't got laminitis. So the paradox of PPID is what I work on why these horses have a high ACTH, which is meant to stimulate the adrenal glands to produce cortisol, and they seem to have symptoms of cortisol excess.

That's why we called it Cushing's disease in the first place, but they have more normal cortisol levels. I won't dwell on this too much, but this is just my, my area of interest. There's some suggestion that it's inactive ACTH, but my data suggests it's probably not.

There's an increased cortisol clearance by the liver, so increased cortisol in the urine definitely. And there may be these active metabolites of cortisol, which I showed in metabolic syndrome cases. So keep an eye out for, for, work that we're going to publish, soon to, to show that, there's other stuff going on in PPID that we don't really understand.

So, this is just to show you that the stress response is a perfectly normal response. So you have the hypothalamus releases cortico releasing hormone to stimulate the pituitary produce ACTH and it's this excess ACTH that is causing the problem. And what I look at is the downstream effects here of having too much cortisol and the effects of cortisol on the tissue, but I won't dwell on that today.

Feel free to ask me any questions on that. But I just thought it'd be nice for you to revise your second year endocrinology at this stage. So let's go on to diagnosis, and, at the moment, we use basal ACTH, so a non-stimulated ACTH is a, is a good screening method.

But as I just said, ACH is a stress hormone. You have to have ACTH to produce cortisol, to respond to stress, and you want to respond to stress because it, it, it's all, it's better all around as an animal to respond to stress. So, Be careful, that a high ACTH is not associated with a significant stress.

So a stress response to illness or travel or extreme excitement, if you've chased that horse around that stable 16 times in order to get the blood sample, you may have elevated the ACTH slightly. And an elevation ACTH is not always a sign of pathology. So my key key point here is interpret the blood sample in association with the horse.

Look at the horse. The symptoms of PPID are classic the hirsutism, insulin dysregulation, changes in fat metabolism, and yes, they might be subtle to begin with, but that doesn't mean to say, that, that you should just interpret the blood sample. You must interpret it in the light of the horse, treat the horse, not the blood sample.

So you get seasonal variety in ACTH. I think everyone knows about. You get this rise in the autumn.

And so we have, seasonal reference ranges, which is, which is great now, please use a validated laboratory and, as again, same with insulin, use the same, lab for the for the horse, so that you can compare between between the groups and it's good as a monitoring tool, but interestingly if your owner is one. It depends what your owner is wanting to do. If they want you to diagnose PPID, then this is a good test to start with.

If they want to know if their horses is likely to get laminitis from their PPID, then this is probably actually not the best test. I certainly wouldn't not do it, but probably the best test is insulin and test of insulin dysregulation. And that's something we're increasingly becoming aware of that we can't necessarily predict laminitic risk from ACTH.

We have to predict it from insulin and, and certainly my work showed that that it doesn't matter what your ACTH is, it matters what your insulin is if you're going to predict laminitic risk. So we could do dynamic testing again, the same, not all horses have a high basal ACTH. Some horses may just be have a have a post response ACTH elevation.

So the classic test is a low dose dex dexamethasone suppression test to detect the failure of suppression of cortisone after administration of dex. So you're testing that negative feedback loop that I showed you earlier. It's a good test.

It shouldn't be, sniffed at. It's not, as, gold standard as it used to be thought of as, but it's certainly a useful dynamic test and slightly easier, to get hold of dexamethasone than it is to get hold of TRH, . But TRH stimulating test is the is the kind of the most commonly used now after basal ACTH so you give TRH and unfortunately we don't quite know how how it works, but you give TRH and you get an elevation in ACTH about 10 minutes afterwards, so it's a fairly easy test to do but getting hold of TRH can be slightly more difficult.

And it's probably best if you can't get hold of it to talk of your talk to your local referring, referral centre to see if, if they have it, or you could do a low dose text me depression test. Sometimes we combine the two, and that makes it more complicated and more likely to be done in a, in a research setting. But, it, it can tell you a lot of things, some, some different factors, than, than, than other things, than just the, TRH and the low dose dex, but, it's certainly interesting.

I think it's important when you're talking to owners, to, to understand that there are other things going on in PPID as well as just the high ACTH. So routine haematology and biochemistry are rarely identified to diagnose PPID, but if these horses are older, I would certainly encourage you to check their liver function, and, and check their, . Check that they're not suffering from any, renal disease or liver disease, or that that's not explaining the, the clinical signs.

For example, if the horse is presented with exercise intolerance or lethargy, which can be a, a, a common presenting sign. So we know that horses have with PPID have impaired neutrophil functions, so they might be more susceptible to, to infections and, and often that's the first sign, you know, a horse with a chronic, sinusitis that just never gets better, test it for PPID and equally a horse of PPID just test that it hasn't got anything else going on. There's a little bit of evidence that shows that, suspensory ligament weakness might be more prevalent in horses with PPID, and, and they may therefore be more susceptible to rupture of the ligament or tendon damage, .

As they get older, but it's difficult to remove age as a confounding factor from PPID itself. But certainly we know that having excess cortisol in your tissues does does affect your, your protein metabolism. And there have been case reports of other conditions in association with PPID.

So fluke infestation, for example, at the moment is, it is certainly being being described in horses with PPID, and it's certainly worth, again, as I say, that's that's why I'm talking about it with the routine haematology and biochemistry, certainly worth checking. if you have a horse that you're suspicious of, always think of the endocrine system is, is what I'd say. So AlfheimMSH is a really good test for PPID actually, but it's not commercially available.

Unfortunately, I use it to diagnose it in, in my cases, but it has to be done in a radioactive immuno's not, not commercially available. Urine, urine was discarded as not being very useful. The corticoid to creatinine ratio is generally higher on horses, but it seemed to have a low sensitivity and specificity.

But, I would say that, work we're doing now on cortisol metabolites, which I showed you earlier in the horse's metabolic syndrome, may, that may prove, to be important in the diagnosis in future. Wait and see. We're, we're working on it, but.

Hopefully, we'll have some better tests. But really, you have to ask what you're testing for. As I said earlier, test for insulin dysregulation is much more important than the ACTH level at the end of the day, and, if you're wanting to predict laminitic risk.

OK, so just finally now we're going to move on to treatment. the treatment is pretty classic in PPID, but it's important to say that not all horses with PPID require treatment. Intervention is only required if the clinical signs compromise the animal's welfare.

So if you've tested it for regulation and it's fine and it's just a bit hairy, but it's perfectly happy and the owners are happy with its performance and There's no real problems with it, then a horse can have PPID without being treated, and I think it just needs to be monitored and make sure that the clinical signs don't impact the horse's welfare because treatment is a lifelong thing. It, it doesn't cure the disease, it just reduces the production of POMC peptides from the melanotrope. So, we're, we're not, we're not fixing the situation.

We're just dampening it down. And if we don't need to at the early stages, then, then we don't need to. Treatment is often recommended an attempt to reduce the risk of laminitis, if it's, not, developed already.

there is, however, very little evidence that the current treatment options actually reduce the risk of laminitis. They may help with managing the insulin dysregulation and therefore, That might be a reason, but they don't have a direct impact on laminitic risk, unfortunately. So the licence treatment, and I'm sorry, this is in the UK.

I understand we have international audiences, but the, the licenced product in the UK is Pergolide, so this acts by reintroducing that dopamine inhibition to the pars intermedia, as I said earlier, an attempt to restore the inhibition. And it's associated with reductions in ACTH in most but not all horses. So don't be necessarily surprised if, if you don't get a reduction, and, hopefully it will improve clinical signs, but not all horses are susceptible, and it does have some side effects if you go at very high doses, such as, colic and, and inhabitants.

Typeptin triste aren't used very commonly. Trista inhibits, the production of, of cortisol by the adrenals, but it, and it improves clinical signs, but it's expensive and doesn't work in all horses. I think dietary regulation, this is the last point I'll, I'll end on.

Dietary regulation is, is really important. So, particularly if the horse is insulin dysregulated, it needs to be on a low carbohydrate diet, and it can be difficult to convince the owners of this if the horse looks poor, but PPID horses often look skinny or look underweight because they've lost muscle and not because they've lost fat. They've normally redistributed that fat into the internal organs and and in the in the peritoneum and certainly when we Postmortem horses with PPID, they have a lot of adipose tissue internally.

So I would say if the horse is in is regulated, please keep it on a low, a low carbohydrate diet, and if you need to improve its energy intake, then you can do that with oil, supplementation, something like that. But you do need to keep those sugar spikes down in horses with PPID who are at risk of laminitis because they have insulin dysregulation. And I could go on for a long time, but I'm going to stop there and take any questions.

I think Sophia, will have been fielding your questions. If you have any, I'm delighted to take them now. Yeah, thank you very much for, really, really interesting talk.

And it's quite amazing just how much, everything's changing in this field actually, so. So a few questions have come through. So one, I think relating to EMS, because it came up, fairly early on.

So which test do you actually think is best if, you know, you know, if the client doesn't have much money, or is it just a case that you as the vet, understand the test more so than which test you're actually using to diagnose the, insulin dysregulation? Yeah, so if the client doesn't have much money, I know it's really difficult, I would do combine a basal insulin test probably with an oral glucose, test. So I would test them prior to give them the oral glucose, and that way you get a a T.

Measurements you get an insulin at baseline and then you get an insulin at 2 hours later and and that obviously that adds as a visit another visit or maybe you could combine it with seeing other horses on the yard or something like that so that you can. Hang around to get that second blood sample, but that's probably the, the cheapest way to get the, the most out of it, but then saying that a CGIT is actually not that expensive depending on how you cost it so, and it gives you probably maximal, information about whole body insulin resistance I sound like I'm sitting on the fence here and I am a little bit in the sense that . You can, you can pick as long as you understand is all I'm saying, and, and as long as you explain to the owners that you might get false negatives in these tests, and but equally I think you should go with your gut if you genuinely believe that this horse or you know that this horse is really, really fat.

And the horse doesn't and the owner doesn't have any money, then you can still implement a diet and exercise plan without testing its insulin. You just can't give them a number which says how, how likely they are to get laminitis, but you know, it's not rocket science. The fat horse is more likely to get laminitis than the non-fat horse.

So, go with, go with your gut as it were. Yeah. And, so, and then monitoring these cases.

So, you know, you've, you've, you found that, there's evidence of insulin dysregulation, it's a fat horse, you implement, you know, diet modification, exercise increases, etc. How often would you recommend that you're, you're testing, or do you just literally, again, you can use your gut and just look at, look at the horse rather than having to repeatedly, to see if the regulation is actually resolving? Yeah, so I think if the owner is compliant and on board and has wanted you to test previously, you should retest to show that you're getting an improvement and also to check owner compliance, and that you know if you're not convinced the horse is losing weight you could test insulin and see if it's becoming better.

I usually tend to wait 6 to 8 weeks after implementing a plan. I like to regularly check in with my owners. I know not everybody has time to do that, but or maybe get your owner.

To say right, you have to email me every 2 weeks, and give me your body condition score of the horse and a picture of the horse, and owners really like that. They like to get on board with that, and if they feel they are accountable, just like people going to Weight Watchers weighed every week, that accountability induces compliance. So, I would do that with an owner and then I would probably test do insulin testing every 6 to 8 weeks, .

Or just once again, and if you've seen a drastic improvement, great, and you say to your owner, gold star, and we'll keep going with it. Yeah. Yeah.

And then very, very quickly, because we are out of time. Feed companies, are they the cause or could they be, could they actually help resolve? Are they advocating that people are feeding too much to their horses, or do you think we could work better with equine nutritionists with the feed companies to address obesity issues within the horse population?

That's quite a big question. It is quite a big question. And I probably get myself into trouble.

So I often describe metabolic syndrome as the very cheapest disease to treat because you don't need to feed them anything and you don't need to put a rug on them and you need to exercise and loads so you get your money's worth out of having a horse. So, if you're being really simple about it, then no, you don't need any input from feed companies necessarily. But then saying that, I recognise that.

People manage their horses in really different ways and that they have situations where the horse has to be stabled all day and what am I gonna do and maybe it can have a forage supplement that is low in sugar and, and I definitely recommend if your horse is on soaked hay using a a a low calorie balancer, which a few companies do really well, so they definitely have their place and I'm not sure we're at the stage where we have a laminitic diet yet because just like. Human weight loss. Yes, if there was a magic diet, we would all take it, but really we just need to eat less and exercise more.

Yeah, brilliant. Thank you, thank you very much. Really interesting talk and thanks for answering those questions.