Equine metabolic syndrome: How can we intervene earlier?

Last November during the Frank J. Milne State-of-the-Art Lecture at the 57th Annual American Association of Equine Practitioners (AAEP) Convention, Oklahoma State University PhD student Heidi Banse, DVM, Dipl. ACVIM, was one of two inaugural recipients of a $5,000 fellowship to support her endeavors in equine research. The AAEP Foundation and The EQUUS Foundation have partnered to support this fellowship, which seeks to assist equine researchers in exploring horse healthcare topics.

According to the AAEP, Banse's doctoral research, performed under the direction of Dianne McFarlane, DVM, PhD, Dipl. ACVIM, focuses on the molecular events underlying equine metabolic syndrome (EMS). Middle-aged horses are most commonly affected by this endocrine disorder, which results in obesity, regional adiposity, insulin resistance and a predisposition to laminitis. If we can identify the metabolic events that lead to EMS, we may be able to diagnose and treat it earlier, resulting in a better outcome. Banse's long-term goal is to identify an intervention for horses with EMS that is based on better knowledge of endocrine disorder's pathophysiology.

Equine metabolic syndrome: An overview

Obesity (body condition score of 8 or 9) (Photo 1), regional adiposity (on the neck crest, tail head, prepuce, mammary gland region) (Photo 2) and insulin resistance are all associated with EMS, a condition associated with a predisposition to laminitis (Photo 3). However, the molecular events underlying how laminitis develops in these horses is still not fully understood. EMS most commonly occurs in Morgan horses, Paso Finos, Arabians, Saddlebreds, Quarter horses, Tennessee Walkers and ponies. Most horses with EMS within these breeds are "easy-keepers"—likely to easily put on excessive body weight despite feed restriction.

Photo 1: An obese horse with EMS. (Photos courtesy of Dr. Banse)

Pasture-associated laminitis is common, as access to new rapidly growing spring pasture with a high water-soluble carbohydrate content can allow for high-energy intake and the development of obesity. When horses graze such pasture, increased resting plasma insulin often results.

Photo 2: Regional adipose tissue on a pony’s neck.

In a recent report, Nicholas Frank, DVM, PhD, Department of Large Animal Clinical Sciences, University of Tennessee's College of Veterinary Medicine suggested that for these animals, "hyperinsulinemia is the trigger for disease."1 He also noted, "Pasture grazing also raises the risk of intestinal carbohydrate overload, particularly when animals are moved onto new pastures without gradual transition."

Photo 3: Laminitis in the same pony as in Photo 2.

This allows for increased high-energy substrate for the lower gut fermentation, which increases lactic acid concentrations, decreases pH and raises mucosal permeability. This may lead to an increase of various toxins and pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1-beta) in the circulation and a potential inflammatory response—in other words, laminitis.

Banse's research—cell metabolism

In people, mechanisms associated with insulin resistance and metabolic syndrome include mitochondrial dysfunction, oxidative stress, increased intracellular lipid accumulation and inflammation. The goal of Banse's research is to determine the mechanism of insulin resistance associated with EMS.

Banse's research to date has focused on metabolic gene expression in horses and markers of mitochondrial dysfunction. Thus far, there has not been evidence that expression of genes involved in glucose and lipid metabolism are impaired with obesity and insulin resistance in horses. Furthermore, indirect evaluation of mitochondria within skeletal muscle has not demonstrated a role of impaired mitochondrial function in insulin resistance in the horse.

A lot of research in EMS that has been done has involved horses that are obese but not necessarily those that fulfill the definition of EMS, with a history of laminitis.

"Much of what we know about EMS is derived from insulin-resistance horses," says Banse. "What has been established is that horses with insulin resistance have a dysregulation of the insulin pathway. Research out of Ohio State University has demonstrated that the number of glucose transporter vesicles within the cell is unchanged, but there are not as many on the cell surface in horses with insulin resistance compared with those that are not insulin resistant."

Further work is needed to clarify the mechanism responsible for the failure of the glucose transporter to reach the cell surface. In addition, it is important to determine whether horses with clinical EMS are similar to those with obesity and insulin resistance only.

Another issue that people have been looking at is the presence of inflammation in horses with insulin resistance and EMS. In people, there is evidence that inflammation promotes insulin resistance. However, thus far, "there hasn't been a lot of data to indicate that inflammation is associated with EMS in the horse," says Banse. Furthermore, studies examining the role of inflammation in insulin resistance and obesity have yielded mixed results. The role of inflammation with both insulin resistance and EMS will continue to be investigated.

"Since there are breeds that are predisposed to EMS, it does indicate that there may be some genetic basis for the syndrome," Banse says. The University of Minnesota has an ongoing large-scale study designed to determine the genetic basis for EMS. The results of this study may provide future directions for research into the pathophysiology of EMS in horses of all breeds.

"We're doing our studies in a step-wise fashion," says Banse, "looking first broadly at the role of metabolic pathways, insulin signaling, inflammation and mitochondrial function in the skeletal muscle in horses with obesity, insulin resistance and EMS. We will let the results of our ongoing experiments lead us toward the area that looks most promising. At this point, it is not clear which of the pathologic mechanisms we will be pursuing as our work progresses."

Ed Kane, PhD, is a researcher and consultant in animal nutrition. He is an author and editor on nutrition, physiology and veterinary medicine with a background in horses, pets and livestock. Kane is based in Seattle.

Reference

1. Frank N. Equine metabolic syndrome. Vet Clin North Am Equine Pract 2011;27(1):73-92.