Tuesday, June 13, 2017

AHF Research Funds at Work: Genetics of Equine Metabolic Syndrome in Arabian Horses

genetics of laminitis and equine metabolic syndrome


AHF laminitis research
Laminitis research takes a lot of twists and turns. The Animal Health Foundation has funded a very diverse array of studies over the years, from growing different types of pasture in Colorado to the most delicate molecular analysis of the lamina’s basement membrane. We’ve looked at ways to directly deliver medication to the foot and ways to analyze the inner workings of the digestive tract’s insulin regulation system.
Some of AHF’s most specialized research has looked at laminitis statistics in the different breeds of horses. Since Equine Metabolic Syndrome is best treated with prevention, it’s important to find ways to identify which horses are most at risk. Sometimes there are no outward signs to indicate which horses will be affected by endocrine-related laminitis as a result of Equine Metabolic Syndrome. Why does one obese horse have laminitis and another doesn’t?
Most of the research is done in sterile laboratories, or on powerful computers that analyze gigabytes of data in a matter of seconds. But if you think all laminitis researchers are clad in white coats and work in ivory towers, think again: Because a lot of them look just like our donors.
Researcher Samantha Brooks genetics of laminitis
The University of Florida's Dr Samantha
Brooks is a genetics researcher with
a special interest in laminitis. (University
of Florida photo)
Samantha Brooks, PhD, of the Brooks Equine Genetics Laboratory at the University of Florida’s Department of Animal Sciences recently published her latest research completed with AHF funding assistance. She specializes in analyzing and isolating aspects of the equine “genome”, or the genetic code in a horse’s DNA, and is particularly interested in which horses may be genetically predisposed to insulin resistance and laminitis associated with equine metabolic syndrome.
Brooks’ state of the art gene analysis work--known in science circles as metabogenomics--has measured chemical signatures in horses’ blood in hopes of generating new targets for early diagnosis and treatment.
The University of Florida data analysis revealed significant genetic markers in the laminitis cases, found near a single candidate gene (FAM174A) that may play a role in cholesterol homeostasis.
But for her current study, Dr. Brooks utilized a legion of assistant researchers who don’t own white coats and may never have crunched more than their holiday shopping data on a hard drive. She didn’t advertise in a medical journal; she put out a call through the equestrian grapevine. The word reached the people she needed.


Arabian horse evaluation during laminitis research project
University of Florida researchers examined horses, took body measurements and analyzed DNA of Arabian horses entered into the study by their owners.

Her assistants were Arabian horse owners in Florida. Their job description required willingness to allow their horses’ DNA codes to be analyzed. Her study needed horses that were at least ten years old and she wanted both horses that were normal and those who were struggling with weight issues. University staff created a profile for each horse, along with hair samples, a medical history, and the horse’s Arabian pedigree. Seven body measurements were taken on each horse, as well.
This study is what is called a GWAS, or genome-wide association study, in research-speak.  Professor Brooks was interested in the genetic code of Arabian horses with a history of severe laminitis secondary to Equine Metabolic Syndrome. Her data analysis revealed significant genetic markers in the laminitis cases, found near a single candidate gene (FAM174A) that may play a role in cholesterol homeostasis.
The best marker she found, known as BIEC2-263524, was correlated with elevated insulin values and increased frequency of laminitis.
Laminitis Memorial Wall hosted by AHF
Do you remember a horse who should be on
The Wall? Click here to put them there!
That data set was then compared to the second population of Arabian horses, most of which had not yet developed laminitis. In these horses, the same marker, BIEC2-263524,  maintained its associations with higher modified insulin-to-glucose ratio  values and body condition score. The markers showed consistency and it should be possible to create an assay test to diagnose Arabian horses with a genetic predisposition to develop obesity.
Professor Brooks is confident enough in her discovery to suggest that FAM174A function may play a role in furthering our understanding of laminitis and perhaps even be helpful in studying metabolic- and obesity-related disorders in other species. 
Her staff of volunteer horseowner research facilitators can take pride in a job well done, and a legacy that may help horses far into the future.

• • • • •

The Arabian horse study is published in the Journal of Animal Science. Click the title link below to visit the abstract page; full access to the paper requires journal sign-in, library access, or purchase but the abstract is free to all to read.

Genomewide association study reveals a risk locus for equine metabolic syndrome in the Arabian horse.Lewis, S. L., H. M. Holl, C. Streeter, C. Posbergh, B. J. Schanbacher, N. J. Place, M. F. Mallicote, M. T. Long, and S. A. Brooks. 2017.
J. Anim. Sci.
95:1071-1079.
doi:10.2527/jas.2016.1221
laminitis research through Animal Health Foundation
Click this link to go directly to the AHF Donation Page.

Monday, August 22, 2016

Mission Accomplished: AHF’s Australian “Pasture Project” Should Unravel the Influence of Paddock Grass Improvement on Laminitis

laminitis research animal health foundation


It's another notch in the belt that is tightening around the disease of equine laminitis. In 2016, the Animal Health Foundation funded a study at Australia's Queensland University of Technology to test the effects of fertilizing or "improving" pasture grass in paddocks where horses with Equine Metabolic Syndrome (EMS) will be grazing.

The study is conducted by Professor Martin Sillence and Melody De Laat, DVM, PhD. The team will investigate the role of pasture improvement in the insulin response to grazing in a herd of ponies with EMS, and compare it to normal ponies.

Determining which factors potentiate insulin responses to forage feeding in horses will enable more accurate assessment of laminitis risk. Further, determining which pastures are safe, and which ones pose a significant risk to horses and ponies will help mitigate laminitis risk more effectively.

Recently, QUT's Director of Alumni and Development, Simone Garske, wrote to Dr. Don Walsh, founder of the Animal Health Foundation and thanked him for the AHF funds, which total $97,593.41 in Australian Dollars ($75,000 in US Dollars).

Large and small (mostly small) donations to the Animal Health Foundation from concerned horse owners and professionals has made research like this possible. This is an example of a research with direct and immediate benefit to horse owners.

You can play a role in the war on laminitis. Click the "donate" button or contact AHF to be part the effort to end this disease. Or, remember a horse with a donation to the Laminitis Memorial list.



Wednesday, June 29, 2016

Your Donation at Work: AHF Funds Laminitis Research on New Drugs for Insulin Dysregulation at Tufts


One of two 2016 AHF laminitis research grants for 2016 will be awarded to Nicholas Frank, DVM, PhD, DACVIM, Professor of Large Animal Internal Medicine at Cummings School of Veterinary Medicine, Tufts University, in Massachusetts. His proposal, "Safety and Efficacy of Two New Drugs for Managing Insulin Dysregulation in Horses" was chosen from among the studies submitted to AHF over the winter.

Dr. Frank's co-investigators include a postdoctoral associate, Sarah Cass, at Tufts and two associates at the University of Massachusetts at Amherst: Director of Equine Management Cassandra Uricchio and Professor Carlos Gradil.

Nick Frank of the Cummings
School of Veterinary Medicine,
Tufts University
The research team in Massachusetts plans to investigate two drugs that are used to treat endocrine disorders in humans are candidate therapies for managing insulin dysregulation (ID) in horses. These drugs have very different mechanisms of action: one lowers blood glucose concentrations by blocking the reabsorption of glucose in the kidney and the other inhibits insulin secretion from beta cells of the pancreas.

It is likely that one or both drugs will be developed into veterinary pharmaceuticals in the future, but this cannot be assumed and the approval process takes years to complete. There is an urgent need for new treatments for ID in horses.

Both medications are already available for use in humans and can be prescribed to horses as extra-label medications. Dr. Frank will evaluate these new drugs and obtain information to guide their potential use in horses and ponies.

What is insulin dysregulation?
Insulin dysregulation is the key component of equine metabolic syndrome (EMS), a collection of risk factors associated with the development of laminitis in horses and ponies. Equids with ID have higher than normal insulin concentrations when feeding (postprandial hyperinsulinemia) and laminitis is thought to develop when hyperinsulinemia occurs for extended periods of time in horses and ponies grazing on pasture.

Fasting hyperinsulinemia and tissue insulin resistance (IR) are also detected in animals with more advanced ID.

What is the benefit to laminitis research of this study?
It is our overall hypothesis that these medications can be used as single or combined therapies for managing postprandial hyperinsulinemia in horses and ponies, and that improved management of hyperinsulinemia will lower the risk of laminitis.

What are the goals of this study?
The specific aims of the study are:
1) To evaluate the safety and dosing of these two medications in horses.
2) To compare normal horses and horses with ID and assess the impact of the medications (each administered alone) on resting and postprandial insulin and glucose concentrations.
3) To determine whether one or both medications alter active glucagon-like peptide-1 (aGLP-1) concentrations during oral sugar tests in horses.
How will you conduct this study?
The study will be conducted by administering the medications to Morgan horses (three normal; three with ID) in dose escalation studies. This project will be conducted at the University of Massachusetts at Amherst.

Congratulations to Dr. Frank and his team.

Photo of Dr. Frank courtesy of Richard Booth.

Your donation at work: AHF Funds Endocrinopathic Laminitis Research at Penn Vet



One of two AHF laminitis research grants for 2016 will be awarded to Penn Vet Senior Research Investigator, Hannah Galantino-Homer, VMD, PhD. Her proposed study, "Epidermal stress in the pathogenesis and diagnosis of endocrinopathy-associated laminitis" was selected from a group of submissions.

Dr. Galantino-Homer's research team will include co-investigators Lynne Cassimeris of Lehigh University, Julie Engiles of Penn Vet, and Robert Clark of Cumberland County College.


Introduction
The most common risk factors for laminitis in horses are excess pasture, obesity, and diseases that affect the horse’s metabolism, including equine Cushing’s disease and equine metabolic syndrome. These diseases and equine obesity share common features with human pre-diabetes/metabolic syndrome.

Penn Vet's Hannah Galantino-
Homer will conduct her
research at New Bolton Center.
Specifically, the metabolic diseases, obesity, and excess pasture are all associated with elevated blood levels of insulin, the endocrine hormone that allows the body to use glucose. We now know that high insulin itself is a laminitis risk factor and insulin alone can induce laminitis in horses and ponies when it is experimentally elevated for a prolonged period. This is known as the hyperinsulinemia model of laminitis.

Several theories of how insulin causes endocrinopathy-associated laminitis (EAL) have been suggested in equine research. However, efforts to pinpoint the exact mechanism have been elusive.

The Laminitis Discovery Database
The investigators on this project have been applying their combined expertise in laminitis research, veterinary pathology, cell biology, protein biochemistry and histopathology to the complex problem of EAL through the use of the Laminitis Discovery Database. This “database” is the group’s archive of samples and information from naturally-occurring and experimental laminitis cases and controls. These data and samples have been collected for several years.


Background on this project
Previous molecular studies of the hyperinsulinemia model of laminitis at Penn Vet revealed changes in lamellar tissue that were consistent with over-stimulation of cellular processes. This over-stimulation leads to cell and tissue stress, damage, and loss of mechanical integrity, consistent with the failure of digital support that is the hallmark of laminitis.

The Penn Vet group became interested in how their results compare to the literature on an increasing number of metabolic, degenerative, and inflammatory human diseases in which chronic overstimulation of cellular processes leads to cell death, tissue damage and ultimately, an inflammatory response to the tissue damage. The group documented molecular evidence of cell overstimulation and cell stress in naturally-occurring EAL cases from the Laminitis Discovery Database.

They also detected changes in the same markers of cell overstimulation and stress that have been found to mediate several important human diseases and that are targets for drugs that could be applied to the prevention and treatment of EAL.

High-magnification images of hoof lamina from Dr. Galantino-Homer's Laminitis Laboratory at Penn Vet's New Bolton Center have transcended science to be exhibited as art. The horse’s hoof normal lamellae, shown here,  consist of primary and secondary folds, resembling a pine tree. This unique evolutionary adaptation increases the contact area between the hoof and underlying tissues, allowing the transfer of the horse’s weight from the bones of the limb to the hoof. As horses evolved from animals with five toes to much larger animals with just one toe, this increased folding of the inner hoof was necessary to maintain hoof attachment. (image courtesy of Dr. Galantino-Homer)

Why is this study needed to improve prevention or treatment of laminitis?
This study will allow the group to determine if the processes already documented in the Laminitis Discovery Database are important at the earliest stages of EAL. They will also determine if the lamellar tissue damage caused by EAL results in the release of keratin proteins into the blood; these proteins could serve as diagnostic biomarkers for laminitis.


What is the direct benefit of this study?
This knowledge would help in the early diagnosis of EAL and in determining the extent of lamellar tissue damage in affected horses. This study will improve our understanding of why EAL occurs, and it will open new doors to the prevention, treatment, and diagnosis of this common and devastating disease.

Congratulations to Dr. Galantino-Homer and her team.

Wednesday, February 17, 2016

Animal Health Foundation Calls for 2016 Laminitis Research Proposals

As spring laminitis season approaches, AHF's laminitis research program is preparing to jump a step ahead. 

The Animal Health Foundation, a US charity based near St. Louis, Missouri, has announced that its first round of open funding for 2016 will begin this spring. The foundation posted a request for research applications on February 10, 2016. 

In 2016, AHF seeks to fund one-year pilot research project proposals that address the cause(s), pathophysiology, early diagnosis, and/or treatment of equine laminitis. 

The basic facts of the proposal requisites include:
  1. Two grants will be made, providing funding up to $25,000 (US) each. 
  2. Funding decisions will be announced on June 1, 2016.
  3. Criteria: research that 1) advances basic scientific understanding of the disease, 2) improves animal husbandry to reduce disease incidence or manage chronic laminitis, or 3) develops clinical diagnostic tools and treatments for equine laminitis.
  4. The term of each grant is one year.
  5. The application deadline is April 15, 2016.

Some of the previous recipients of AHF grants include:
  • Dr. Chris Pollitt, University of Queensland, Australian Equine Laminitis Research Unit
  • Dr. Melody De Laat, Queensland University of Technology
  • Dr. Martin Sillence, Queensland University of Technology
  • Dr. Nick Frank, Cummings School of Veterinary Medicine at Tufts University
  • Dr. Phil Johnson, University of Missouri College of Veterinary Medicine
  • Kathryn Watts, BS, Rocky Mountain Research, Colorado
  • Dr. Samantha Brooks, Brooks Equine Genetics Laboratory, Cornell University (now at the University of Florida)
  • Dr. Steve Adair, University of Tennessee at Knoxville
  • Dr. Tom Goetz, University of Illinois
  • Dr. Harold Garner, University of Missouri
  • Dr. John Bertram, Cornell University
  • Dr. Eleanor Green, University of Missouri (now at Texas A&M University)

Click here to download the 2016 prospectus for AHF grant applicants. Only grant applications adhering to the specifications in the prospectus will be considered.

Correspondence about the 2016 grants and the Foundation should be directed to Dr. Don Walsh: walshvet@gmail.com.

About the Animal Health Foundation: AHF is a quiet but effective source of laminitis research funding. Since its founding in 1985 by Don Walsh, DVM, AHF has fueled laminitis research with more than $1.8 million of funding for key projects in North America and Australia. More information is available on the Foundation's website, http://www.ahf-laminitis.org.

AHF began as a group of horse lovers and owners who wanted to make a difference by establishing the AHF to fund laminitis research. AHF is not-for-profit and has no paid employees. Donations to the AHF are tax deductible. Contributors can be assured that their contributions truly work directly toward the goal of ending laminitis suffering by horses. The administrative costs incurred by the AHF are below 4% annually. All administrative costs are paid for by the Board of Directors, so 100% of what you donate will go directly to fund laminitis research.

Sunday, January 31, 2016

AHF's Dr. Donald Walsh Receives Missouri Horse Shows Association Distinguished Lifetime Service Award

Missouri Horse Shows Association award

At the annual meeting of the Missouri Horse Shows Association on January 30th at the Peachtree Banquet Center in Columbia, Missouri, Dr. Donald Walsh received the association's Jeff Shikles Memorial Distinguished Service Award for his work in laminitis research and education through founding the Animal Health Foundation.

The Missouri Horse Shows Association offers year-end and high point awards in more than 140 divisions to member exhibitors and nominated horses. MHSA is an affiliate member of the United States Equestrian Federation.

Dr. Walsh is the founder of the Animal Health Foundation and a lifelong resident of Missouri. He showed Saddlebred horses in his youth. He is a graduate of the University of Missouri College of Veterinary Medicine, and established Homestead Veterinary Hospital in Pacific, Missouri in the 1980s. He is now retired from daily practice and is dedicated to the advancement of laminitis research and education through the Animal Health Foundaiton.

The presentation was made by Dr. Nancy Roth, far left, assisted by Dr. Philip Johnson of the University of Missouri College of Veterinary Medicine, holding certificate. Dr. Johnson's laminitis research has been funded by the Animal Health Foundation in the past. Dr. Walsh is holding the MHSA award plaque and sculptured horse head of the perpetual trophy. On the far right is Homestead Veterinary Hospital's Dr. Mark Cassells, president of the Animal Health Foundation. The photo was taken at the annual MHSA awards banquet in Columbia Missouri on Saturday, January 30, 2016. (photo by Diana Walsh)

Monday, November 30, 2015

AHF-funded laminitis research proves role of the equine gastrointestinal system in high insulin levels and laminitis risk


The Animal Health Foundation is pleased to announce the publication of a new study funded by donations to AHF's laminitis research fund. This study demonstrated that the digestive system contributes to high insulin levels and laminitis risk in some ponies. "Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation" was published earlier this month by the American Physiological Society, and is summarized here.

Researcher Melody de Laat, PhD, BVSc and Professor Martin Sillence, PhD from Queensland University of Technology in Australia recently completed an Animal Health Foundation funded investigation of some of the gastrointestinal factors proposed to play an important role in causing hyperinsulinaemia (high blood insulin levels) in ponies.

The aim of the study was to determine what contribution specialized gastrointestinal hormones, called incretins, make to the insulin response to carbohydrate-rich meals in ponies. During the study, they examined the insulin and incretin responses to sugar when it was given orally and intravenously in a group of ponies, as well as the ponies' responses to standard commercial grain meals.

Background

The glucose contained in feed is released and absorbed from the small intestine into the bloodstream after eating; it stimulates the pancreas to release insulin. Insulin ensures that glucose is taken up into cells where it is either used for energy production or stored for later use.

During obesity or equine metabolic syndrome, this process becomes abnormal ("insulin dysregulation"), and more insulin than usual is released after eating. High insulin concentrations in horses/ponies can increase a horse or pony’s risk of laminitis.

Incretin hormones are produced by special cells in the small intestine after a meal is eaten. These hormones, called GLP-1 and GIP, stimulate the pancreas so that it produces even more insulin than it would normally, in response to glucose. The additive effect of incretin hormones on insulin production has not been determined previously in ponies, but it was known that incretins can increase insulin production substantially in other species.



Primary results

Drs de Laat and Sillence confirmed that hyperinsulinaemic ponies (ponies with abnormally high insulin levels), after consuming a carbohydrate-rich meal, also had high concentrations of the active form of the incretin GLP-1. 

However, normal ponies secreted much less GLP-1. 

Another incretin hormone, GIP, was also increased by a high-carbohydrate meal in ponies, but it was not different between normal and hyperinsulinaemic ponies. 

Importance of findings

These findings are important because drugs that can block the action of GLP-1 at its receptor can now be investigated as a treatment for reducing hyperinsulinaemia in horses. Dr de Laat and her team are currently busy in the laboratory working on this!

However, despite confirming a significant role for the incretins, overall the study found that glucose was the most important stimulator of insulin production in ponies following a meal. The study also found that hyperinsulinaemic ponies absorb more glucose from their feed than normal ponies, and Drs de Laat and Sillence are continuing to investigate the differences in glucose absorption between normal and hyperinsulinaemic ponies.

Additional findings

Given that the researchers found that the digestive system plays an important role in hyperinsulinaemia, they also wanted to investigate whether ponies that had insulin dysregulation always also suffered from tissue resistance to the actions of insulin (insulin resistance). 

They found that ponies could have abnormally high insulin responses to a high-carbohydrate diet repeatedly, but still be classified as normal on an intravenous test for insulin resistance. This important finding indicates that the problem of hyperinsulinaemia in horses likely originates in the gut rather than in other tissues, and that this is where future investigations should focus. 



Changes in testing
Furthermore, the results indicate that veterinarians should use oral sugar tests when assessing a horse or pony for equine metabolic syndrome, rather than intravenous tests, so that the test results include an assessment of the gastrointestinal system. 

Importance of study

By showing that hyperinsulinaemia can occur independently of tissue insulin resistance, Drs de Laat and Sillence confirmed that gastrointestinal factors are a very important part of insulin dysregulation in ponies.

Article © 2015 Animal Health Foundation. No use without permission. 

The Animal Health Foundation is interested in how the hormone insulin is regulated and utlized in the horse. We are funding extensive research in Australia in this area and welcome you to join us in supporting this project. Your large and small donations are welcome.

You may use the "donate" button in the sidebar to make your donation, or click on the "donate" tab at the top of the page for more options. The AHF Memorial Wall is another way to make a donation, by remembering a horse whose name will be posted with yours on our growing memorial wall. Your donation will go directly to fund laminitis research. Thank you.




To learn more:

Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation
Melody A de Laat, James M McGree, Martin N. Sillence
American Journal of Physiology - Endocrinology and Metabolism Published online 3 November 2015
DOI:10.1152/ajpendo.00362.2015


Note: the study was published online by the American Physiological Society and will appear in a future edition of the Society's journal.