Overview of Equine Metabolic Syndrome
(Insulin dysregulation syndrome, Equine syndrome X, Peripheral Cushing disease)
Equine metabolic syndrome (EMS) describes a characteristic collection of clinical signs and clinicopathologic changes in equids. It is found in both horses and ponies and has also been recognized in donkeys. Affected animals typically are obese, with increased condition score overall and increased adiposity in the neck and tailhead regions. Laminitis, both chronic and acute, is common. Hyperinsulinemia with normal blood glucose concentrations (insulin resistance) is the primary clinical pathologic finding. Other associated signs include infertility, altered ovarian activity, and increased appetite. Other laboratory findings include hypertriglyceridemia, increased serum concentrations of leptin, and arterial hypertension. Previously, this cluster of clinical signs in horses was referred to as hypothyroidism, peripheral Cushing disease, prelaminitic syndrome, or Syndrome X. EMS replaces these earlier terms. EMS may be the end result of an inability to properly metabolize dietary carbohydrate, and many horses exhibit exaggerated glucose and insulin responses to an oral hexose load before developing true insulin resistance. Any abnormality in carbohydrate metabolism in horses has been termed insulin dysregulation.
EMS first develops in horses 5–16 yr old. Breeds most commonly affected include ponies, Saddlebred, Tennessee Walking, Paso Fino, Morgan, Mustang, and Quarter horses. Thoroughbreds and Standardbreds infrequently develop EMS. There is no recognized sex predilection.
The underlying reason why some horses develop EMS and others do not is not known. There appears to be a genetic disposition, both within and between breeds. Affected horses may possess a “thrifty” gene that enabled their ancestors to survive in harsh environments. This increased efficiency of energy metabolism became maladaptive in modern environments with plentiful, nutrient-dense feedstuffs.
The common denominators behind many of the signs associated with EMS appear to be increased adiposity, insulin resistance, and hyperinsulemia. When obesity develops, adipose tissues elaborate leptin and other adipokines as well as tumor necrosis factor and other inflammatory mediators. Increased fat stores in the liver may also predispose to insulin resistance due to down-regulation of insulin receptors.
Experimentally, high blood insulin levels lead to laminitis in horses and ponies. Insulin has vasoregulatory actions. Insulin resistance can decrease nitric oxide production and promote vasoconstriction. Altered glucose and insulin levels may also lead to altered epidermal cell function and glucose uptake by epidermal laminar cells. These effects predispose horses with EMS to develop laminitis.
Horses with EMS respond to high carbohydrate meals with an exaggerated increase in insulin, a higher than expected blood glucose level, and a very slow return of blood glucose concentrations to baseline values. This indicates a resistance to the peripheral effects of insulin (EMS) and/or an inability to metabolize oral carbohydrate normally (insulin dysregulation).
EMS may be a predisposing factor for pituitary pars intermedia dysfunction (PPID; also called equine Cushing disease). Both endocrine disorders can occur concurrently in middle-aged and older horses. Horses with EMS should therefore be monitored to detect the onset of PPID. (Also see Hirsutism Associated with Adenomas of the Pars Intermedia.)
There is no clinical picture that is pathognomonic for insulin resistance. Horses may exhibit all the phenotypic characteristics of EMS with normal responses to evocative testing. In most instances, the animals in question are obese because of excess calorie intake rather than any underlying metabolic alteration.
Affected horses typically are obese with a body condition score >6 out of 9. Even if the overall condition score is not extremely high, there is increased fat deposition in the neck, leading to a “cresty” appearance. Fat deposition over the ribs and over the top line to the tail head is also common. Geldings may have increased fat deposition in the prepuce, whereas mares may have increased fat deposition around the mammary gland. Laminitis is a common finding. Horses brought in for evaluation with no previous history of laminitis often show evidence of prior episodes such as abnormal hoof growth rings and radiographic evidence of third phalanx rotation or pedal osteitis. Laminitis may occur secondary to ingestion of feeds high in soluble carbohydrates, either in the form of lush pasture or high-carbohydrate hays and supplements. This can result in bouts of laminitis developing in the spring, when new pasture growth appears, and in the fall, when night temperatures are below freezing.
Horses with EMS may not lose weight without extreme feed restriction; owners commonly report that affected horses remain obese even when fed minimal amounts. Obesity may be exacerbated by laminitis, which may limit exercise. Horses appear to have increased appetites and often will eat continually as long as feed is available. Infertility and abnormal reproductive cycles occur in mares affected with EMS.
Diagnostic testing for EMS should concentrate on documenting insulin resistance while excluding PPID. The presence of obesity and the cresty neck phenotype is not sufficient to make a diagnosis. A careful dietary history and physical examination are essential. Establishing baseline body condition score and neck circumference will enable assessment of the horse’s response to treatment. Even if there is no history of laminitis, careful examination of the feet, including lateral images of P3, are indicated.
Because many conditions, including diet, pain, and stress, can affect blood glucose and insulin levels, diagnostic testing should be performed in a controlled manner in a low-stress environment. If the horse has laminitis, diagnostic testing should be delayed until the feet have stabilized and are relatively pain free.
Blood glucose concentrations are in the normal range or only slightly increased with EMS. If persistent hyperglycemia is documented, concurrent PPID should be strongly suspected. Because many factors influence blood glucose and insulin levels, a one-time blood insulin measurement should be used only as a screening test for insulin resistance. Insulin should be determined after the horse has been fasted for 6–8 hr. This can be done by leaving only one flake of hay with the horse after 10 PM the night before and then collecting the blood sample the next morning. If those conditions are met, a blood insulin concentration >20 μU/mL is suggestive of insulin resistance.
To document insulin resistance, the horse’s ability to handle glucose should be evaluated. Because a subset of horses are normal in all respects except for their ability to handle an oral carbohydrate load, an oral sugar test (OST) or oral glucose test (OGT) should be performed. The OST is easy to perform in North America, where corn syrup is readily available, whereas the OGT can be performed in other parts of the world. The OST is performed by fasting the horse for 6–8 hr and then giving an oral dose of corn syrup at 0.15 mL/kg. Blood should be collected at 60 or 90 min after administration of the corn syrup for insulin determination. An insulin concentration >60 mU/L is abnormal. The OGT is performed by giving a fasted horse 0.5 kg of chaff-based feed to which dextrose powder at 1 g/kg has been added. An insulin concentration >87 mU/L in a blood sample collected 2 hr later is abnormal. To determine whether insulin can stimulate normal glucose uptake by peripheral tissues, an insulin tolerance test can be performed. This is accomplished by collecting a baseline blood sample for glucose concentration, giving regular human recombinant insulin at 0.1 IU/kg, IV, and then collecting a second blood sample for glucose concentration 30 min later. A second blood glucose concentration that does not decrease to 50% or less of the baseline value indicates insulin resistance. Other diagnostic testing that has been described includes the IV glucose tolerance test or a combined glucose-insulin response test. The oral glucose tolerance test can be altered by delayed gastric emptying or poor GI absorption and is less desirable. Because of the large number of blood samples required and the fact that change from baseline—not absolute glucose values—is of interest, a hand-held glucometer to determine blood glucose concentration may be used when performing these tests.
Tests for PPID such as measuring endogenous ACTH concentration, the dexamethasone suppression test, domperidone response test,or thyroid releasing hormone response test are normal in horses with EMS. Positive results indicate that the horse is concurrently affected by EMS and PPID, which can occur in older horses. Detection of PPID is important, because it is thought that PPID exacerbates insulin resistance in horses previously affected by EMS.
Treatment for EMS involves dietary management and, if diet and exercise is not sufficient to treat the condition, medical therapy. Correction of the diet may be all that is needed to return the horse to normal body weight. Dietary carbohydrate restriction is essential to decrease glycemic and insulinemic response; total calorie intake is restricted to reduce body weight. Pasture access should be eliminated or severely restricted. Use of a grazing muzzle may aid in decreasing pasture ingestion.
The nonstructural carbohydrate (NSC) content of forage should be determined by feed analysis. This can be calculated by adding starch and water-soluble carbohydrate percentages. Ideally, NSC should comprise <10% of the hay dry matter, and it should never exceed 16%. Soaking hay in water for 60 min has been recommended to lower water-soluble carbohydrate concentrations, but the actual amount reduced is extremely variable; hence, this is not a reliable method to produce a low-NSC forage. Supplements should be given to add needed vitamins and minerals but not additional calories. Complete feeds that are formulated to be low in digestible energy and carbohydrate specifically designed for horses with insulin resistance may be used in place of forage and supplements. Numerous dietary supplements have been suggested to increase insulin sensitivity, including cinnamon, chromium, and magnesium. None has been shown to improve insulin sensitivity in horses in experimental situations.
Horses should initially be fed 1.5% of their ideal body weight in forage per day. This amount can be lowered to 1.25% and then to 1% of ideal body weight after 30 days, if necessary. Sudden feed restriction should be avoided, because it may lead to hyperlipemia and further exacerbate insulin resistance. Increasing the amount and level of exercise will increase the rate of weight loss. The amount of exercise necessary to provide maximal benefits has not been established, but five sessions per week that include at least 30 min of trotting and lunging is a realistic goal. In horses with laminitis, walking as pain allows may be of some benefit.
Weight reduction should be documented by scale weight or weight tapes. In addition, neck thickness and diameter can be monitored over time. If increased exercise and dietary modification is not sufficient to decrease body weight, medical therapy may be of benefit.
The thyroid hormone thyroxine, in the form of levothyroxine sodium, will accelerate weight loss and thereby improve insulin sensitivity when combined with dietary interventions in horses. Horses weighing >350 kg can be given 48 mg/day, PO; smaller horses and ponies should receive 24 mg/day, PO. Treatment periods of 3–6 mo are often needed to achieve desirable weight loss. At that time, the horse should be weaned off the medication over 3–4 wk. If feed intake is not limited concurrently, treatment with levothyroxine is unlikely to resolve clinical signs.
Metformin is poorly absorbed in equids but may decrease postprandial glucose and insulin levels.. It may lead to improvement in hyperinsulinemic horses at a dosage of 30 mg/kg, PO, tid or bid. It should be given 30 min before a meal if possible. However, the longterm efficacy and safety of metformin has not been established in horses. If it is used, blood glucose should be carefully monitored. Use of metformin should be discontinued if hypoglycemia is documented.
Prevention of EMS should focus on maintaining normal weight in horses, particularly in high-risk breeds. Because these horses may be more efficient users of ingested calories than others, it is imperative to feed appropriately to maintain an ideal condition score and not to use arbitrary feeding guidelines. Particular care should be exercised when turning horses on pasture during times of high-soluble carbohydrate content, eg, spring and autumn.