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January 21, 2020 – Dr. Kelly Diehl talks with Dr. Molly McCue, Associate Dean of Research, and Professor, at the University of Minnesota. They discuss equine metabolic syndrome, a serious and increasingly common disease in horses. Dr. McCue also discusses her Foundation-funded research to better define the syndrome and understand its risk factors.

00:18 Dr. Kelly Diehl: Welcome to Fresh Scoop, Episode 16: What We Know and Don't Know About equine metabolic syndrome. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation's Senior Director of Science and Communication and today, we'll talk with Dr. Molly McCue, Associate Dean of Research and professor at the University of Minnesota, a Morris Animal Foundation funded researcher and Molly's the former chairperson of our large animal advisory board.

00:46 DD: Fresh Scoop is the monthly podcast of Morris Animal Foundation. One of the largest non-profit foundations in the world dedicated to funding studies to find solutions for serious health threats to animals. In each episode we'll feature one of the researchers we fund or one of our staff members, discussing their work in advancing animal health.

01:06 DD: Whether you're a practicing veterinarian, technician or student or just an animal-loving science geek, Fresh Scoop is the podcast for you. You can learn more about us at morrisanimalfoundation.org.

01:20 DD: Okay, on to today's show and as I mentioned, we're going to be speaking with Dr. Molly McCue. Dr. McCue completed her DVM at Kansas State University before moving to The University of Georgia for her internship. Then she returned back to Kansas State for her residency in equine internal medicine and then moved to the University of Minnesota whereas I mentioned, she is today.

01:44 DD: She did her PhD and post-doctoral training there at the University of Minnesota. She is also a multi-foundation funded researcher. [chuckle] Molly's got a lot of grants from us over the years and her interest is in using molecular genetics and genomics to explore equine diseases.

02:05 DD: Today, we'll be focusing on her work with equine metabolic syndrome and Molly, thanks for joining us today.

02:12 Dr. Molly McCue: Thank you Kelly, for having me.

02:14 DD: Before we get into your work, we always start with a little personal story and so, if you could tell us a little bit about yourself, beyond what I just mentioned and how you came to veterinary medicine.

02:27 DM: Well, in all honesty Kelly, I never wanted to be anything besides an equine veterinarian. That was the first job that I wanted when my parents broke it to me when I was about four that I couldn't grow up and be a puppy.

[laughter]

02:40 DM: That was disappointing but once I got over the trauma of that, I decided I wanted to be a veterinarian and horses have always been my focus and I never really wavered from that career goal over time. I think I just added additional things besides just being a veterinarian to my list.

03:00 DD: Right and how did you get interested in equine genetics?

03:09 DM: My interest in equine genetics, in part, was shaped by the opportunities that I had when I came to the University of Minnesota to do my PhD and then also because I had learned during my master's degree that I really liked statistics and math and applying statistics in epidemiology or the study of diseases and populations towards my work and genetics actually was a melding of what I had done previously with some more molecular work than I had done in my previous training.

03:44 DD: Cool. As you may or may not know, most of our listeners are non-horse-owners and tend to be small animal veterinary practitioners who are probably pretty far away from their equine rotations at vet school. So can you start by defining what equine metabolic syndrome is?

04:00 DM: Sure. equine metabolic syndrome, while we often shorthand call it a disease, it's really a mix of a set of clinical signs that we see in horses. The ones that are most obvious, I think that most people associate with the syndrome are obesity and a predisposition to developing laminitis or founder is the lay-term that's often used, but inflammation in the hooves but the way that we define the syndrome now is we actually measure 11 traits in these horses and the combination of abnormalities across those traits would be how we define metabolic syndrome and it's really...

04:45 DM: The terminology came up because of the similarities to metabolic syndrome in people where obesity and some other things have been identified sort of pre type 2 diabetes and/or for cardiovascular risk so we really borrowed the term for the syndrome and have spent a lot of time trying to understand exactly what it is.

05:07 DD: Just thinking about that and I'm really going to date myself for being in vet school 30 years ago but I was just a mere child then but I have a question about, is this a new disease or is it an unrecognized disease? Because unless I was falling asleep in the back of the room, I do not remember really learn... I mean certainly, you learn about laminitis but I don't remember really learning at all about equine metabolic syndrome.

05:37 DM: Yeah, it's not a new disease. I think it's a new term for something that's been happening for a long time. Even when I was in vet school, it was right after I graduated, I think the first paper that used the terminology 'equine metabolic syndrome' to describe these horses that tend to be fat and laminitic. It's been around for a while but we didn't call it equine metabolic syndrome until I think the first paper was in 2001 or something like that where that terminology was used.

06:00 DD: Okay. So more recent terminology and for everyone who's listening and for good review for me as well, what horse breeds tend to be predisposed or is this something that affects all horse breeds?

06:30 DM: It's something that can affect horses of any breed but we do know that there are some breeds that we think of more typically. Certainly any of the pony breeds tend to be at higher risk. Morgan horses, Arabian horses, some people describe Saddlebreds and Tennessee Walking horses to be at higher risk. I would say that it's probably easier to list the breeds that may be of lower risk so we see this less frequently in breeds such as the Thoroughbred, the Quarter horse and the Standardbred than we see in many of our other riding horse breeds but it really is an issue for horses of any breed.

07:15 DD: Okay so that makes me think of a potential genetic component to it since it seems to be in certain breeds and as you know, we of course see diseases in dogs and cats, cats not so much because the domestic short hair is pretty much what we see most of the time but the same in dogs and we'll loop around to your research but is there, what you're finding, a suspected genetic component to this?

07:47 DM: Yeah. It definitely has a genetic component and actually, that's where we first got involved in studying equine metabolic syndrome. Right as I was finishing my PhD and becoming a brand new baby faculty member, I was approached by Ray Geor who has been a fantastic collaborator of mine through most of my career as a faculty member, interested about could there be a genetic predisposition to the disease and so we really got into this disease because of that question. We had the hypothesis that it was genetic but interesting, we just published a paper earlier this year which is the first paper that really proved what proportion of metabolic syndrome risk was genetics. It's taken us a while to get there and prove our hypothesis and feel like we had very solid data but it's definitely genetic.

08:47 DD: Okay. What is a percent that you found in your paper?

08:53 DM: Yeah, we had a paper that we published that looked at the heritabilities of this disease. The first author on this paper is a PhD student in my lab, Elaine Norton, who's just about finished up with her PhD studies and what we did was look at the heritability or an approximation of the percent of disease that's due to genetics across 11 different traits that we associate with metabolic syndrome, things like their fasting blood glucose and their fasting insulin levels and across those traits, we looked in both Welsh ponies and Morgan horses and we saw that there was variability in that genetic percentage, anywhere from around 32% to greater than 80%, depending on the trait and on the breed. So overall, what could sum that up by saying we would call it a moderately heritable trait, moderately to highly heritable trait in both the Morgans and the Welsh ponies.

09:56 DD: Okay so is this a disease that we created by selecting horses for certain traits? We think about that sometimes, especially for me, we talk about that a lot in dogs. Like we see cancer obviously, in certain breeds of dogs and the question is "Well, is what makes a golden retriever a certain phenotype, what unfortunately we brought along with that is potential for a cancer" thinking of them of course and is this something... Did we create this or do you think this is... I know you said this disease has probably been around for a long time but is it an ancient disease? I mean we know laminitis was described thousands of years ago but is this... Or is this something we've created more recently?

10:50 DM: It's a great question and it's one sort of after an area that's a big interest of mine. I think we... For a very long time, once we domesticated the horse, we being humans, we selected individuals that were really thrifty. We didn't have to feed them a lot, they could do quite a bit of work on relatively sparse feedstuffs and then when horses transitioned sort of in that post-World War II area from being work animals to being recreational animals, they didn't need to be so metabolically efficient and we also had the ability to feed them more and we improved grasses, we improved grains and so we've created this problem in many ways on two fronts. One by our genetic selection and two by the environment that we exposed them to.

11:43 DM: It's a great question. It's not the only disease in domestic animals that we would... The answer would be the same for. We have described other diseases in horses and then of course in dogs and cats. That question is one that we think about quite a bit so definitely in this disease, things that we have done, both in their genetics and their environmental management have increased the incidence and risk for this disease.

12:12 DD: That's really interesting because I didn't think about that, that transition period after World War II. We'll loop back a little bit and tell everyone what the signs of equine metabolic syndrome are. We talked about laminitis but that's not clearly the only sign.

12:28 DM: Yeah so really obesity and laminitis are the two overt clinical signs that we can see just looking at the animals. When we measure biochemical characteristics, they tend to have higher fasting insulin concentrations. They tend to have an exaggerated insulin response to glucose stimulation that could be using something like an oral glucose tolerance test, which would be really similar to what they do in people or it could be an intravenous or injection of glucose into the bloodstream. Their insulin responses are quite high and then we see things like, elevated in their serum triglycerides so one of the fats that you can measure in the serum are higher in these animals than a normal horse and we see also an increase in some of their fat hormones. We see an increase in their fat hormone leptin and we see a decrease in their fat hormone adiponectin so their adipokines are abnormal.

13:39 DD: Which is similar in people, if I remember, correct?

13:42 DM: Yeah.

13:43 DD: Okay.

13:43 DM: Yeah, correct.

13:46 DD: Why did you choose to look at this particular disease and you've alluded to it but can you elaborate on why this disease is so important to horses right now?

13:58 DM: Yeah. We chose to look at this disease for a couple of reasons. I think the first one is that it's a very common problem in horses so depending on the study or depending on the part of the world, we're talking 20% to 30% of horses and probably... Or greater, would be diagnosed with some component of this syndrome and so that's one thing, it's common and then the second thing that I think makes it extremely important to horse health and horse medicine is a lot of times, laminitis can be a really devastating downstream effect of having these metabolic abnormalities.

14:39 DM: Some of these horses have sort of acute laminitic episodes and recover from them but many of them develop chronic laminitis and it's one of the most common reasons that horses can no longer perform their task in life, be that to be a riding horse or something else and it's also a very common reason that we have to euthanize horses because they're so painful and the condition can't be managed so to me, it was important to really get a handle on what was happening, what were the early changes before horses develop laminitis so we could start making recommendations to keep that from happening in these horses.

15:20 DD: So what preventive measures can people take, first of all and if... and then, how do you treat this condition?

15:31 DM: I think, the biggest things that we know to do right now are doing things like making sure that their diet is... they don't have excessive calories in their diet so controlling their diet. Matching that with a controlled exercise. There have been some studies that show, for example, horses that are grazing particular times a year, particularly when there's early and lush growth of pastures, there's higher sugar in the pastures, that probably predisposes them so individuals that are predisposed, doing things like not letting them graze on Spring grass early in the Spring or if you happen to be some place where your rapid grass growth is in the Fall, making sure that the animals don't have unlimited access to pasture and then exercising. Making sure that, again, they're doing enough exercise that they don't have a sort of calorie overload relative to the amount of exercise that they're performing.

16:35 DM: Those are the things that we know to do right now. We may talk about this more later but some of our work that was funded by Morris Animal Foundation has also shown that things like exposure to organic pollutants, these would be residues from pesticides and other agricultural chemicals, are associated with changes and abnormalities in some of the measurements of metabolic syndrome. There's the potential for doing things like making sure they're not exposed to excessive environmental toxins.

17:07 DM: I think one of our goals in this research and understanding the underlying genetics, sort of the underlying problem that they have that then results in metabolic abnormalities is to answer the question of "can we provide more targeted treatments than changing their management or managing their laminitis once it happens?"

17:27 DD: And that was a good lead-in because that was my next question of... Which was a little bit about talking about your research, which has been, if I could summarize it for the people listening, it's a good example of how difficult it is to pin down and cone down on really complex diseases. It's sort of like the Marine course of, you go over the wall, then you jump through a hoop, then you go in the mud, then you go, right? [chuckle]

17:55 DM: [chuckle] Exactly.

17:56 DD: You swing from the branch and so I am going to ask you to give us an overview and you just talked about one of your studies of all this work you've done to come to that paper really, right?

18:11 DM: Right.

18:11 DD: With the risk factors and can you give an overview, just really quickly, like the hoop you jumped through first and then the wall you climbed over and then the mud you ran through to get to that point.

18:25 DM: Yeah, I love the way that you describe it because it has felt very much like that. When we first had conversations about pursuing this line of research, it was like "Well, we should look at the genetics of equine metabolic syndrome" which sounds like a really straightforward thing but as we started to really understand what we knew about the disease, what we should be looking at, it turned out that step one was we didn't even really have a good definition of what are the components or what are those traits that add up, sum together to be the components of metabolic syndrome. How are we going to define these horses?

19:03 DM: I mentioned earlier it's a syndrome so it's a mixing of clinical signs. It's not really a "has disease / does not have disease" designation. We realized that the first thing that we needed to do was sample a very large population of horses and understand what is the variation in things like fasting insulin and glucose. What's the variation and leptin or at adiponectin levels? What do we expect in an animal that we would consider clinically normal? What are the ranges that we see in horses that are obese and have laminitis or have one and not the other?

19:41 DM: Because as we really were drilling down to it, how are we going to pick our cases or controls, for example, for genetic study, we realized we don't know enough about this disease to answer that question and along with that, we had a secondary question of, would we expect these levels to be different in different breeds? We know there's differences in breed risk for metabolic syndrome so we thought we better figure out is the normal insulin value different in a Corda Horse than it is in a normal Morgan Horse and how do we take that into account?

20:16 DM: That was step one, looking at about 900 horses across 20 different breeds and trying to understand what are the expected values for these traits and that's how we got down to saying there's nine biochemical measures and then the presence or absence of laminitis and then some measurement of obesity that we thought were really important to understand as components of the syndrome so that was step one and when we did that, we recognized that we were right, there were breed differences in some of those traits and so we needed to really consider, do we need to look at the genetics in more than one breed? And so, it's probably... Looking back now because you alluded to this earlier, Morris has funded us for several projects along the way but one of the earliest projects was saying, we would really like to look at the Welsh Pony and the Morgan Horse and look at the genetics and those two breeds, recognizing that ponies overall are at a higher risk than horse breeds and that some of their measurements look different and that the Morgan Horses would be a good representative of high-risk horse breeds for lack of a better way to do it.

21:32 DM: That was the second study, gathering all of that data and gathering data about genetic markers so we could do things like the paper we published earlier this year to talk about the heritability and then we have from there done something we call a genome-wide association study so we don't expect that it's one gene that's controlling this syndrome. We expect that there's alleles across many genes, that it's a complex trait and so we have been looking to try to better explain this complex trait and we've just finished the genome-wide association study and we know that there are about 2,000 genes that likely across the genome between those two breeds that'll be important for controlling an animal's risk factor and that's sort of where we are today.

22:24 DM: Along the way, we've done a couple of different things. I alluded to the study where we looked at the organic pollutants and that's because we realized very early on, we measured all the exercise these horses did, everything that they ate, tried to explain the environments and how that was impacting their risk and we realized we were missing something so we went on a search for what was that missing piece in the environment and that's how we found that it was organic pollutants and we know that that's important in metabolic syndrome in people.

22:56 DM: And then another example was we recognized that ponies and horses were really different and we have found a gene that's one of the major... There's an allele and a gene that's a major controller of height in horses so very common in what makes ponies shorter and have shorter stature and we were able to show that that gene is also impacting metabolic traits and what was nice about that story too is that in humans, we know people of shorter stature have higher risk for metabolic syndrome and type two diabetes. It turns out that horses have shorter stature, which we call ponies, have the same risk and it's actually the same genetic mutation that makes them short but also increases their risk.

23:41 DM: So we've come a long ways and we've gone from 20,000 genes in the genome down to a couple of thousand to look at and now we have to find the actual mutations or alleles in those genes that we have to look at next. That's sort of where we are today and it's easy to talk about in three minutes but this is 11 years that we've been working on this now.

24:00 DD: [chuckle] Yeah, a long time which actually brings me to a question I was going to ask you later but this is a good lead-in to it, which is now that you've got to this point, where do you go next? What are you going to do in the future?

24:13 DM: Yeah, so where do we go next? Right now what we are doing and it's happening at this moment in my lab, is we took 40 individuals from both the Welsh pony and Morgan breeds and we sequenced their entire genome and so in those individuals, we know some of them are normal and some of them, we would classify as metabolic syndrome and so using that genome sequencing, we're starting to look for any alleles or mutations within these 2,000 genes to say we think this is the actual change right down to the single base pair position in the genome that's contributing to this trait.

24:58 DM: Once we've identified those alleles. Like I said, that's what's happening now, we're looking in 40 individuals because it's too expensive to sequence. I think we're now up to 1,200 horses to sequence all of their genomes. It's still too expensive today, although that might not be the case in the near future but what we want to do is look at those alleles and then create a genotyping assay to test those alleles across the 1,200 horses we have and make a decision about which ones are most important and once we know which ones are most important, we can develop a genetic test where we can look at a foal the day it's born and say, this foal has a very low risk during its life it's ever going to develop metabolic syndrome and it can be out in green pasture and you can feed it what it wants and it's not a concern versus another one where you can start managing it long before you can detect any changes on blood work or anything like that, to really sort of nip it in the bud and stop the disease before it starts.

25:58 DM: That's where we're headed. That's the ultimate goal and it's still a couple few years of work in front of us but we've come a really long way in our understanding of what's happening in these horses so we feel we're very happy with where we are, I guess with our work over the last decade.

26:19 DD: Right. Do you think this is... you know, you've... talking about genetic tests, do you think this is something we can breed out of horses or it's just not possible?

26:31 DM: It's a great question. When we think about genetic tests that are a single mutation in a single gene, we do have the opportunity to breed away from that single mutation. When we're talking about a complex disease like metabolic syndrome, we're talking about maybe a thousand different mutations that are contributing to an animal's risk and so our goal here really shifts. It shifts away from thinking about just breeding it out of the population to really thinking about, how are we going to take the information that we understand about this animal's genetics and change the way that we manage or treat it over its lifetime to try to prevent disease and so when I'm talking to people, the best example that I would give is when you look at things like in humans, breast cancer risk alleles so if you happen to have a mutation that increases your risk, nobody tells you that that's a death sentence and you're going to get cancer and it's all over.

27:32 DM: What your physician tells you is you have a higher risk so we need to do earlier screenings. So we would do, for example, mammograms at an earlier age and more frequently than somebody who didn't have that same genetic risk. The same idea applies here. An animal with a very low risk, we can probably not have to worry too much about management as long as it's not getting incredibly obese and it could be out on green pasture. We're not worried about the lifetime risk of laminitis, whereas a horse that, we think based on its genetics has a very high risk, we would be giving advice about not having that horse be on pasture, making sure that feed is limited, considering to do things like test the environment for toxins and try to mitigate that sort of thing because the combination of both the environment and the genetics in that animal mean that it has a high likelihood of getting disease.

28:26 DD: And that leads into, what do you think... For everyone who's listening and we'll have some horse owners and some equine veterinarians and everybody, what do you think the take-home message is from what you've seen so far and what you've learned about equine metabolic syndrome?

28:46 DM: I think the take-home message is we can't completely mitigate a horse's risk. There are people who believe that this is all because we feed them too much and all because they're obese. I think the take-home message, to me, it's probably a couple of small things, is there's a genetic predisposition to this disease. We need to recognize those individuals who are predisposed and we need to change the way that we manage them before there's ever an indication of abnormal blood work or laminitis and that if we can do that effectively, we can keep them from having a problem and they can live longer and healthier lives.

29:27 DM: That's really the goal and the take-home. I think it's possible and we're very close to really realizing that vision.

29:39 DD: That, I think, is a really good point. I think that's something we're learning about obesity in people and dogs too. Is that shaming dog owners, which was how we addressed obesity, I think, for a long time is not really productive nor realistic nor fair and it's really interesting to hear that probably the same thing goes on in horses and so there's a behavior, I think and a psychological component here that we can help horse owners understand.

30:11 DM: Exactly.

30:12 DD: So my last question is a little bit off the beaten track but I'm just wondering, is this a problem in other equids? When you think of wild horses or zebras or is this really unique to the domesticated horse?

30:31 DM: I think it's a great question. I can tell you that I know of individual cases. For example, zebras in captivity that have a problem because they are provided too many calories that have similar sort of downstream problems. We've seen it in donkeys. We've seen it in equid hybrids like mules. I think that it's likely, whether or not it's the exact same genetic alleles that are controlling it. It's possible that some of these are really ancient alleles that were before the division of equids. It makes sense again, if you're living in the wild, you are definitely going to have selective pressures to make you very metabolically efficient so as soon as we bring them into an environment in which they have excess calories provided, they definitely can develop this syndrome.

31:26 DD: That's super interesting. I know that your work will really make a big difference in horses and you've already done that and all your work in genetics because I know you do others and for everyone who's listening, Molly has also trained up... I don't know how many people you have trained... That have branched out into different areas of equine genetics and are really changing the field so I appreciate Molly, all the work you've done for our horse health because it's impactful from many different ways, not just coming... The stuff coming out of your lab but certainly all the people you've trained and the good friend you've been to the Foundation over the years and all of the work you do for us so thanks and keep up the good work.

32:16 DD: It's been really, really impressive and thanks so much for joining us today and telling us about this really, really important disease of horses, I guess syndrome of horses not just disease and we'll look forward to reading more of your work. Molly's a prolific publisher of papers and people from her lab so thanks because it needs to get out there for folks.

32:29 DM: Thanks for having me. Take care.

32:29 DD: That does it for this episode of Fresh Scoop and once again, thanks to Dr. Molly McCue for joining us and we'll be back with another episode next month that we hope you'll find just as informative. The science of animal health, as we know, is ever changing and veterinarians need cutting edge research information really to give their patients the best possible care and that's why we're here and you can find us on iTunesSpotifyGoogle Play Music, and Stitcher and to learn more about Morris Animal Foundation's work, again, go to morrisanimalfoundation.org. There you'll see just how we bridge science and resources to advance the health of animals. You can also follow us on FacebookTwitter, and Instagram and I'm Dr. Kelly Diehl and we'll talk soon.