The term equine metabolic syndrome (EMS) was first introduced to veterinary medicine in 2002 when Johnson1 proposed that obesity, insulin resistance (IR), and laminitis were components of a clinical syndrome recognized in horses and ponies. The study of EMS is therefore in its infancy, so the following consensus statement reflects our current knowledge of this condition. We anticipate that defining features of the EMS phenotype, approaches to diagnostic testing, and management options will be expanded and updated as further research is performed. “EMS” was adopted as the name for this condition because of similarities with the metabolic syndrome (MetS) in humans, which is a collection of risk factors assessed to predict the occurrence of coronary artery disease and type 2 diabetes mellitus in people.2 Despite alternative nomenclature having been proposed previously (eg, peripheral Cushing's syndrome, prelaminitic metabolic syndrome), it was the unanimous decision of the consensus panel to support the use of the term EMS because it has gained wide acceptance and is appropriate when used to define a clinical syndrome unique to equids. The panel proposed that the EMS phenotype for the majority of affected equids should include: Increased adiposity in specific locations (regional adiposity) or generally (obesity). Regional adiposity is characterized by expansion of subcutaneous adipose tissues surrounding the nuchal ligament in the neck (cresty neck), development of fat pads close to the tail head, or fat accumulation behind the shoulder or in the prepuce or mammary gland region. Obesity is observed in the majority of cases, but some affected equids have a leaner overall body condition and regional adiposity, and others are normal in appearance. These different phenotype variations require further study. IR characterized by hyperinsulinemia or abnormal glycemic and insulinemic responses to oral or IV glucose and/or insulin challenges. A predisposition toward laminitis. Clinical or subclinical laminitis that has developed in the absence of recognized causes such as grain overload, colic, colitis, or retained placenta. Additional components of the EMS phenotype that warrant further consideration include: Hypertriglyceridemia or dyslipidemia as a component of EMS in some cases.3–5 Increased very low-density lipoprotein triglyceride concentrations have also been detected in horses with EMS.5 Hyperleptinemia resulting from increased secretion of the hormone leptin by adipocytes in response to IR or a state of leptin resistance.6 Leptin is referred to as a satiety factor because it signals the hypothalamus that a state of energy excess exists within adipose tissues.7 Arterial hypertension4,8 detected in the summer in laminitis-prone ponies,8 which is recognized as a key component of MetS related to IR in humans.9 Altered reproductive cycling in mares. Loss of the seasonal anovulatory period10 and prolongation of the interovulatory period11 have been described in obese insulin-resistant mares. Increased systemic markers of inflammation in association with obesity.12 Contributing factors for obesity should be assessed from the history, including the quantity of feed provided, size and quality of the pasture, and amount of exercise. Horse owners sometimes refer to affected horses and ponies as “easy keepers” or “good doers” because they require a lower plane of nutrition to maintain body weight than other horses. Previous episodes of laminitis may be described in the history. Mild episodes of bilateral laminitis may have been mistakenly attributed to sole bruising, arthritis, or foot soreness after trimming or shoeing. If laminitis episodes have been recognized in the past, it should be noted whether the onset of lameness was associated with changes in the abundance or composition of pasture grass, or alterations in grain feeding. Familial patterns have been recognized for EMS,3 so relevant information about the horse's dam and sire should be collected for future reference. Clinical signs of EMS include regional adiposity, obesity, bilateral lameness attributable to laminitis, and/or evidence of previous laminitis such as divergent growth rings on the hooves. A cresty neck score13 has been developed to assess the expansion of adipose tissues within the neck region and scores range from 0 to 5. Scores ≥3 are often detected in horses or ponies with EMS. The description provided for a score of 3 is “Crest enlarged and thickened, so fat is deposited more heavily in middle of the neck than toward poll and withers, giving a mounded appearance. Crest fills cupped hand and begins losing side-to-side flexibility.” Neck circumference can also be measured at the midpoint of the neck with a tape measure. This measurement is taken halfway between the poll and the withers when the neck is in a normal elevated position.5 The neck circumference-to-height at withers ratio was recently used to predict the development of pasture-associated laminitis in ponies and a cut-off value of >0.71 was established. Body weight should be measured with a scale or weight tape and body condition scoring14 can be used to assess generalized obesity. EMS is a complex disorder for which there are more questions than answers at present. The principal components of EMS are increased adiposity, IR, and laminitis, but this syndrome likely encompasses a much wider spectrum of problems that affect energy metabolism, perturb adipocyte function, promote thrombosis, induce inflammation and oxidant stress, and alter vascular endothelial cell function in affected horses. Environmental (eg, diet, level of physical activity, season) and intrinsic (eg, genetics) factors will affect body fat mass. The mechanisms underlying generalized obesity or regional adiposity in EMS are unknown but chronic overfeeding in association with limited physical activity appears to be a contributing factor. Additionally, horses and ponies with EMS appear to have enhanced metabolic efficiency with respect to the utilization of dietary energy. In this context, it has been suggested that horses and ponies evolutionarily adapted to survival in nutritionally sparse environments are especially predisposed to obesity and IR under modern management conditions in which plentiful feed is available year round. For example, feral and native pony breeds retain strong seasonality with respect to appetite and body condition. Under “feral” conditions these ponies gain weight during the summer months when food is abundant before losing it again during the winter.a Seasonal changes in insulin sensitivity also may occur, reflecting alterations in food availability, physical activity, and body condition. Season affected resting serum insulin concentrations in 1 study of obese mares, with higher concentrations detected in December, compared with September, October, and November.11 In the context of domesticated equids experiencing a chronic state of overnutrition, these seasonal changes in body condition and insulin sensitivity may be replaced by progressive obesity and IR with associated adverse health consequences. More research is required to identify the genetic determinants of metabolic efficiency in horses and the effects of environmental factors such as overnutrition on the expression of these genes. Adipose tissue is no longer regarded as just an energy storage organ, but an endocrine organ producing many hormones (adipokines or adipocytokines).15 Adipose tissue dysfunction (with or without obesity) is an important pathophysiologic feature of MetS in humans that may result in IR, systemic inflammation, hypertension, and a prothrombotic status. Adipokines are released from adipocytes and other cells within fat tissues. They include leptin, resistin, adiponectin, visfatin, and apelin as well as inflammatory cytokines released from macrophages and adipocytes such as tumor necrosis factor alpha (TNFα), interleukins 1 (IL-1) and 6 (IL-6), and macrophage chemoattractant protein 1. The inflammatory adipokines may then lead to a self-perpetuating cycle of enhanced adipose tissue inflammation, adipokine synthesis, and secondary acute phase protein synthesis by the liver. Thus obesity in people is characterized by a state of chronic low-grade inflammation.15 Few data are available on the pathophysiological effects of obesity or regional adiposity in EMS. Obesity has been associated with reduced insulin sensitivity in horses and ponies,3,5,10,11,16 although some obese horses have normal insulin sensitivity. Whether obesity induces IR or the insulin-resistant horse is more predisposed to obesity has not been determined. Further contributory factors to obesity and IR may include altered cortisol metabolism within tissues1 or leptin resistance, a situation in which tissues fail to respond to leptin.7 In humans, mesenteric and omental adipose tissues are thought to play a more important role in the development of type 2 diabetes mellitus than adipose tissues elsewhere because fatty acids and adipokines released from these visceral sites enter the portal circulation and have a more profound effect on hepatic metabolism and insulin clearance.17 This situation is currently being examined in horses to determine whether adipose tissue from the neck crest or abdomen differs from tissues collected from other locations, but results have not yet been published. IR involves defects of insulin signaling such as reduced insulin receptor tyrosine kinase activity and reduced postreceptor phosphorylation steps that impinge on metabolic and vascular effects of insulin.18 There are two primary theories linking obesity to IR: (1) the down-regulation of insulin signaling pathways induced by adipokines and cytokines produced in adipose tissue; and (2) the accumulation of intracellular lipids in insulin-sensitive tissue such as skeletal muscle (lipotoxicity).19 The natural equine diet contains little fat, but excess glucose can be converted into fat via de novo lipogenesis. Fats are used for energy or stored as triglyceride within cells. When the storage capacity of adipose tissues is exceeded, fats are directed toward nonadipose tissues (repartitioning). Skeletal muscle, liver, and pancreatic tissues attempt to utilize fats by increasing β-oxidation, but lipid can accumulate within these tissues and alter normal cellular functions, including insulin signaling. We are limited at present to the knowledge that IR and/or hyperinsulinemia predispose ponies to pasture-associated laminitis and that the condition can be experimentally induced by infusing supraphysiological amounts of insulin IV over 2–3 days.3,20 Potential mechanisms relating obesity, hyperinsulinemia, and IR to laminitis are largely extrapolated from studies in other species and include endothelial cell dysfunction within blood vessels of the foot,21 digital vasoconstriction,22 impaired glucose uptake by epidermal laminar cells,23 altered epidermal cell function or mitosis,24 and matrix metalloproteinase activation by glucose deprivation or reactive oxygen species.23 Insulin has vasoregulatory actions and it was the consensus of the panel that this represents a plausible link between IR and laminitis in horses. Vasodilation normally occurs in response to insulin through the increased synthesis of nitric oxide (NO) by endothelial cells.25,26 However, insulin may also promote vasoconstriction by stimulating the synthesis of endothelin-1 (ET-1)26 and activating the sympathetic nervous system.27 Activation of the insulin receptor stimulates at least two different signaling pathways within the vascular endothelial cell.28 NO is secreted when the phosphatidylinositol 3-kinase (PI3K) pathway is activated, whereas activation of the mitogen-activated protein kinase (MAPK) pathway leads to the release of ET-1. IR states in humans have been found to involve selective pathway inhibition such that the NO synthetic PI3K pathway is inhibited whereas the MAPK pathway is unaffected and may be overstimulated because of compensatory hyperinsulinemia, which results in increased ET-1 synthesis.25,29 Vasoconstriction may therefore be promoted in the insulin-resistant animal as NO production decreases, which might impair the ability of vessels to respond to vascular challenges. To the panel's knowledge, there are no published studies on the epidemiology of EMS although there are a few reports on the prevalence of obesity and hyper-insulinemia in populations of ponies and horses.30,b,c,d-b,c,d Anecdotally, Welsh, Dartmoor, and Shetland ponies and Morgan Horse, Paso Fino, Arabian, Saddlebred, Spanish Mustang, and warmblood breeds appear to be more susceptible to EMS. However, the panel emphasized that EMS can be prevented through good management practices, so breed susceptibility should be viewed accordingly. EMS also occurs in other light horse breeds, including Quarter Horses and Tennessee Walking Horses, but is rarer in Thoroughbreds and Standardbreds. Miniature horses, donkeys, and draft horses require further study to determine the prevalence of EMS in these groups. Susceptibility to EMS may be established from before birth, and obesity develops in some horses as soon as they reach maturity. However, most horses with EMS are between 5 and 15 years of age when veterinary or farrier services are first requested because of laminitis. A seasonal pattern has been identified for laminitis in the United States, with the highest incidence of pasture laminitis around May and June (late spring/early summer).3,31 This seasonal rise in laminitis incidence has been attributed to increased nonstructural carbohydrate (NSC) consumption from pasture forage. In the United Kingdom, the highest incidence of pasture laminitis was during the summer (June and July), when sunshine hours and presumably forage NSC content were greatest.e This observation provides further circumstantial evidence to suggest a link between grass carbohydrate content and laminitis incidence. Serum insulin concentrations and the reciprocal inverse square of insulin proxy estimate of insulin sensitivity measured in ponies predisposed to laminitis suggested a decrease in insulin sensitivity during summer, and this was attributed to changes in pasture carbohydrate composition.8 Results suggested that aspects of the EMS phenotype in ponies may be latent under conditions of lower or restricted dietary water-soluble carbohydrate (WSC) content, but become apparent when carbohydrate intake increases. Pasture carbohydrate content and climate/seasonal effects are inextricably linked. During periods of high sunshine, when sugars are produced in excess of the energy requirement of the pasture for growth and development, they are converted into storage, or reserve, carbohydrates, such as fructans and starches.32 EMS can be diagnosed by obtaining a complete history, performing a physical examination, taking radiographs of the feet, and conducting laboratory tests. Physical examination should include assessment of the horse for evidence of regional adiposity, including adipose tissue expansion within the neck crest, and body condition scoring. Current screening tests for IR focus upon the measurement of glucose and insulin concentrations in single blood samples, although dynamic tests are necessary to properly assess insulin sensitivity. An important goal for the future is the development of a panel of tests to diagnose EMS. Hyperglycemia is rarely detected in horses with EMS because most animals maintain an effective compensatory insulin secretory response in the face of IR. However, blood glucose concentrations are often toward the higher end of reference range indicating partial loss of glycemic control. If persistent hyperglycemia is detected, a diagnosis of diabetes mellitus should be considered. Type 2 diabetes mellitus occurs in horses and may be more common than thought previously.33 This diagnosis should be considered when hyperglycemia cannot be attributed to other causes such as stress, recent feeding, administration of α-2 agonist drugs, or inflammatory processes. Hyperinsulinemia in the absence of confounding factors such as stress, pain, and a recent feed provides evidence of IR in horses and ponies. However, resting insulin concentrations are not found to be increased in all cases, so dynamic testing provides the most accurate diagnosis of IR. It should also be recognized that reference ranges vary among laboratories, in part because of differences in the assay used. More research is required to determine cut-off values for hyperinsulinemia, but a value of 20 μU/mLf is suggested as a general guideline for the upper limit of serum/plasma insulin concentrations in normal horses and ponies. Sampling conditions are important when diagnosing the chronic IR associated with EMS. Cortisol and epinephrine released as a result of pain or stress lower tissue insulin sensitivity and raise resting glucose and insulin concentrations.34,35 Insulin concentrations are likely to be higher in a horse that is currently suffering from laminitis, so testing should be delayed until after the pain and stress of this condition has subsided. Blood samples should be collected after an approximately 6-hour period of feed withholding, ideally between 8:00 and 10:00 am. These conditions can be achieved by providing not more than 1 flake of low-NSC grass hay per 500 kg bodyweight no later than 10:00 pm the night before sampling. Under these conditions, hyperinsulinemia (>20 μU/mL) provides evidence of IR. If hyperinsulinemia is not detected, but other components of the EMS phenotype are recognized, a dynamic test of insulin sensitivity should be performed. Dynamic testing for evaluation of insulin sensitivity is recommended because tissue insensitivity to insulin may only be revealed when glycemic control is challenged by inducing hyperglycemia. A number of tests can be used for this purpose, and an ideal test for diagnosing IR in horses has not been established to date.36 Testing should be conducted under the same conditions as blood sampling for resting glucose and insulin measurements. Horses must be tested after the pain and stress of laminitis has subsided, and after an approximately 6-hour fast to limit confounding effects of recent feed consumption. Oral or IV glucose tolerance tests can be performed to raise blood glucose and insulin concentrations and determine the height and width of the resulting curve. Area under the curve values provide the best measure of glucose tolerance, although the peak concentration and time taken for concentrations to return to baseline can also be evaluated. The combined glucose-insulin test (CGIT) developed by Eiler et al37 can also be used to diagnose IR in horses.5 Insulin is injected immediately after dextrose to lower blood glucose concentrations. Advantages of the CGIT include the shorter time required for testing and information gained about both the glycemic and insulinemic responses. A CGIT is performed by first obtaining a preinjection blood sample for baseline glucose and insulin measurements, and then injecting 150 mg/kg body weight (bwt) 50% dextrose solution IV, immediately followed by 0.10 U/kg bwt regular insulin IV.37 These dosages are equivalent to 150 mL of 500 mg/mL (50%) dextrose and 0.50 mL of 100 U/mL insulin for a horse weighing 500 kg. Insulin should be drawn into a tuberculin syringe and then transferred into a larger syringe containing 1.5-mL sterile saline (0.9% NaCl) before injection. Blood glucose concentrations are measured at 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 120, 135, and 150 minutes postinfusion. When the CGIT is performed in healthy animals, blood glucose concentrations return to below the baseline value by 45 minutes, so preliminary results are available within 1 hour if a glucometer is used. Blood collected at 0 and 45 minutes is submitted for insulin assay and this allows the insulin response to be evaluated. Horses with insulin concentrations >100 μU/mL at 45 minutes are secreting more insulin than normal and/or clearing the hormone from the circulation at a slower rate. This is interpreted as an indication of IR. The test can be abbreviated to 60 minutes when used in the field, but it is advisable to complete all of the measurements so that the horse's complete response can be recorded for future comparison. Hypoglycemia is a potential complication of testing, although this is rarely encountered in the patients selected for testing. If clinical signs of hypoglycemia (sweating, weakness, and muscle fasciculation) are recognized or if blood glucose concentrations fall below 40 mg/dL (2.2 mmol/L), administer 60 mL of 50% dextrose IV and repeat as necessary. In addition to glucose, it has been found that feeding some other carbohydrates to ponies induces an exaggerated insulin response in IR individuals. These carbohydrates include inulin, a type of fructan carbohydrate.38 Furthermore, the administration of dexamethasone also elicits this exaggerated insulin response.5 These observations may have implications for the likely causes of hyperinsulinemia in horses or ponies with EMS that are grazing on pasture, putting them at risk of laminitis. These tests require further validation. Future directions for diagnostic testing include the development of a test panel consisting of assays that can be performed on a single blood sample. Such a panel might further include the adipokines leptin, adiponectin, and resistin, lipids such as triglyceride and nonesterified fatty acids, fructosamine as a reflection of blood glucose concentrations,39 and measures of systemic inflammation including TNFα, IL-1, IL-6, C-reactive protein, serum amyloid A, and plasminogen activator inhibitor-1. Red blood cell count, PCV, iron concentration, and plasma gamma glutamyl transferase (GGT) activity might also be included on the panel. Anemia is sometimes detected in EMS horses, and some affected horses have shown elevated GGT activity that has corresponded with hepatic lipidosis, detected in biopsy and necropsy specimens. Pancreatic insulin secretion may be assessed by measuring serum connecting peptide (C-peptide) concentrations. This peptide is released in equimolar amounts with insulin, but is not cleared from the blood by the liver.40 Approximately 60% of the insulin secreted by the pancreas is extracted from the portal blood by the liver in healthy humans, so hyperinsulinemia can develop as a result of reduced insulin clearance and/or increased pancreatic secretion. Serum C-peptide concentrations can indicate the relative contributions of these processes. Recent research suggests that reduced insulin clearance significantly contributes to hyperinsulinemia in horses with EMS,41 so the C-peptide-to-insulin ratio may be useful to further characterize the hyperinsulinemia detected in equids. Regional adiposity and laminitis are clinical signs of PPID as well as EMS,42 so both endocrine disorders should be considered when these problems are detected. EMS may be differentiated from PPID by: Age of onset: The EMS phenotype is generally first recognized in younger horses, whereas PPID is more common in older horses; although these disorders may coexist. Further clinical signs suggestive of PPID, but not EMS, including delayed or failed shedding of the winter haircoat, hirsutism, excessive sweating, polyuria/polydipsia, and skeletal muscle atrophy.42 Positive diagnostic test results for PPID: For example, detection of an increased plasma adrenocorticotropin hormone concentration in the absence of confounding factors such as pain and stress, and outside of the late summer/autumn period when false positive results occur in healthy horses and ponies.g Reduced glucose tolerance indicative of IR has also been detected in horses with PPID.43 However, it was the consensus of the panel that normal insulin sensitivity is more common in horses with PPID, which suggests that the relationship between these conditions is complex. Discussion of this subject generated several questions that require further research, including: Does IR only accompany PPID when the animal was insulin resistant before pituitary dysfunction developed? If this is the case, PPID may exacerbate IR, but not be the cause of the problem. If PPID causes IR in some horses, but not others, is this a particular manifestation of the disorder? Are specific hormones responsible for IR in these PPID patients? Are the effects of PPID on insulin sensitivity dependent upon the stage of the condition? Does EMS represent a risk factor for PPID? The consensus panel recognized that some equids with EMS subsequently develop PPID, so both conditions can occur concurrently. Anecdotal reports suggest that horses and ponies with EMS are predisposed to PPID and pituitary dysfunction develops at a younger age in affected animals. Further research is required in this area, but the panel recommends that equids with EMS be closely monitored for clinical signs of PPID and undergo regular testing for the condition. If PPID is causing and/or exacerbating IR, treatment should improve insulin sensitivity. Pergolide is recommended for the treatment of PPID in equids.42 Dietary management of EMS involves reducing the amount of energy provided in the diet to induce weight loss if the horse or pony is obese and lowering the NSC content of the diet to reduce glycemic and insulinemic responses to meals. Reducing the digestible energy (DE) content of the diet is an important factor in moderating obesity as a contributory factor to EMS. Limiting or eliminating pasture grass from the diet is a key component of this approach because pasture grazing provides DE that cannot be quantified. Obese horses and ponies should be provided a forage diet with mineral/vitamin supplementation. Hay with low NSC content should be selected, which can be determined by submitting a sample for analysis or by purchasing forage with a declared nutrient analysis. Simple sugars, starches, and fructans are NSC, whereas cellulose and hemicelluloses are structural carbohydrates.32 It was thought previously that fructans undergo minimal hydrolysis until they reach the large intestine of the horse, so they would be less likely to contribute to the glycemic response after a meal. However, there is some evidence indicating that there may be appreciable microbial and acid hydrolysis of fructans before they reach the equine large intestine.32 Furthermore, insulin-resistant ponies exhibit an insulin response to dietary fructans.38 It is therefore recommended that NSC be calculated by adding starch and WSC percentages together, and this value should ideally fall below 10% of dry matter when feeding horses or ponies with EMS. Hay can be soaked in cold water for 60 minutes to lower the WSC content if the amount of NSC exceeds 10%.44 However, a recent study demonstrated that results vary markedly among different hay samples,45 so this strategy cannot be relied upon to completely address the problem of high WSC concentrations in the hay that is being fed to a horse or pony with EMS. Weight loss should be induced in obese horses by restricting the total number of calories consumed and by increasing the individual's level of physical activity. In horses that are being overfed, removal of all concentrates from the diet is sometimes sufficient to induce weight loss. An obese horse should be placed on a diet consisting of hay fed in an amount equivalent to 1.5% of ideal body weight (1.5 lb hay per 100 lb bwt). Hay should be weighed on scales to ensure that correct amounts are fed. If an obese horse or pony fails to lose weight after hay has been fed at an amount equivalent to 1.5% of ideal body weight for 30 days, this amount should be lowered to 1%. However, amounts should not fall below this minimum of 1% and it should be noted that severe calorie restriction may lead to worsening of IR, hyperlipemia, and unacceptable stereotypical behaviors. Pasture access should be eliminated until insulin sensitivity has improved because carbohydrates consumed on pasture can trigger gastrointestinal events that lead to laminitis in susceptible horses.46 Mildly affected horses can return to pasture once obesity and IR have been addressed, but care must be taken to restrict pasture access when the grass is going through dynamic phases, such as rapid growth in the spring or preparation for cold weather in the fall. Measurement of pasture grass NSC content at different times of the day has revealed that grazing in the early morning is likely to be safer for horses with IR, except after a hard frost when grasses accumulate WSC.47 Other risk factors for high fructan content include regular cutting, cool, and bright conditions and predominance of certain grass species such as ryegrass.32,48 Strategies for limiting grass consumption include short (<1 hour) turnout periods (or hand-grazing), confinement in a small paddock, round pen, or area enclosed with electric fence, or use of a grazing muzzle. Horses and ponies with EMS can have rapid rates of grass intake, so >1–2 hours grazing may be excessive for these animals.32 Unfortunately, severely insulin-resistant horses that suffer from recurrent laminitis must be kept off pasture permanently. These patients should be housed in dirt paddocks so that they are able to exercise once hoof structures have stabilized. Forage only diets will not provide adequate protein, minerals, or vitamins. Supplementing the forage diet with a low-calorie commercial ration balancer product that contains sources of high-quality protein and a mixture of vitamins and minerals to balance the low vitamin E, vitamin A, copper, zinc, selenium, and other minerals typically found in mature grass hays is therefore recommended. These products are designed to be fed in small quantities (eg, 0.5–1.0 kg total per day). Insulin-resistant horses with a thinner overall bod
