Year: 2010
Type: article
Abstract: 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 test developed by can also be used to diagnose IR in Insulin is after to lower blood glucose of the include the time required for testing and information gained about the glycemic and insulinemic A is performed by first obtaining a blood for baseline glucose and insulin and then body weight by insulin These are to of 500 and of insulin for a horse 500 Insulin should be into a and then into a before Blood glucose concentrations are measured at and When the is performed in blood glucose concentrations return to the baseline value by so results are available within 1 a is used. Blood collected at 0 and is for insulin assay and this the insulin response to be evaluated. Horses with insulin concentrations at are more insulin than normal and/or the hormone from the circulation at a This is as an of IR. The test can be to when used in the but it is to complete all of the so that the horse's complete response can be for future is a of testing, although this is rarely in the for If clinical signs of and muscle are recognized or blood glucose concentrations of IV and as In to it has been found that some other to ponies induces an insulin response in IR These include a type of the administration of also this insulin These may have for the likely causes of hyperinsulinemia in horses or ponies with EMS that are on pasture, at risk of laminitis. These tests require further for diagnostic testing include the development of a test panel of that can be performed on a single blood a panel might further include the adipokines leptin, adiponectin, and resistin, lipids such as triglyceride and fatty as a of blood glucose and of systemic inflammation including serum and blood cell and activity might also be on the is sometimes detected in EMS horses, and some affected horses have elevated activity that has with hepatic detected in and insulin secretion may be assessed by serum This is released in amounts with but is not from the blood by the of the insulin secreted by the is from the portal blood by the in humans, so hyperinsulinemia can as a result of reduced insulin and/or increased pancreatic Serum concentrations can the of these processes. research that reduced insulin to hyperinsulinemia in horses with so the ratio may be to further the hyperinsulinemia detected in equids. Regional adiposity and laminitis are clinical signs of as well as so endocrine should be considered when these problems are EMS may be from of The EMS phenotype is generally first recognized in horses, whereas is more common in although these may Further clinical signs of but not including delayed or of the and skeletal muscle diagnostic test results for For example, of an increased hormone concentration in the absence of confounding factors such as pain and stress, and of the period when results in horses and glucose tolerance of IR has also been detected in horses with However, it was the consensus of the panel that normal insulin sensitivity is more common in horses with which that the between these conditions is of this questions that require further IR only when the animal was insulin before dysfunction If this is the may IR, but not be the of the If causes IR in some horses, but not is this a of the specific hormones for IR in these the effects of on insulin sensitivity upon the of the EMS a risk factor for The consensus panel recognized that some equids with EMS so conditions can reports suggest that horses and ponies with EMS are predisposed to and dysfunction develops at a age in affected Further research is required in this but the panel that equids with EMS be for clinical signs of and testing for the condition. If is and/or IR, should insulin sensitivity. is recommended for the of in management of EMS involves the amount of energy provided in the diet to induce weight loss the horse or pony is obese and the NSC content of the diet to glycemic and insulinemic responses to the energy content of the diet is an important factor in obesity as a contributory factor to EMS. or pasture grass from the diet is a key component of this because pasture provides that cannot be horses and ponies should be provided a forage diet with with NSC content should be which can be by a for or by forage with a and fructans are whereas and are It was thought previously that fructans until they reach the of the so they be likely to to the glycemic response after a However, there is some evidence indicating that there may be and of fructans before they reach the equine insulin-resistant ponies an insulin response to dietary It is therefore recommended that NSC be by and and this value should ideally of when horses or ponies with EMS. can be in for to lower the content the amount of NSC However, a recent study that results vary among different hay so this cannot be upon to the of high concentrations in the hay that is being to a horse or pony with EMS. loss should be induced in obese horses by the number of and by increasing the level of physical In horses that are being of all from the diet is sometimes to induce weight An obese horse should be on a diet of hay in an amount to of ideal body weight hay per should be on to that amounts are If an obese horse or pony to weight after hay has been at an amount to of ideal body weight for this amount should be to However, amounts should not this of and it should be noted that may lead to of IR, and Pasture should be until insulin sensitivity has because on pasture can that lead to laminitis in susceptible affected horses can return to pasture obesity and IR have been but must be taken to pasture when the grass is through dynamic such as growth in the or for in the of pasture grass NSC content at different of the has revealed that in the is likely to be for horses with IR, after a when accumulate risk factors for high content include and conditions and of grass species such as for grass consumption include periods in a or with or use of a Horses and ponies with EMS can have of grass so hours may be for these insulin-resistant horses that from laminitis must be pasture These should be in so that they are to have only will not provide or the forage diet with a that contains of protein and a of and to the and other found in grass is therefore These are to be in (eg, kg per horses with a overall
Authors: N. Frank, R.J. Geor, S.R. Bailey, A.E. Durham, P.J. Johnson
Language: English
Subfield: Equine
Field: Veterinary
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1550074454