Equine Metabolic Syndrome

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 and by glucose or has and it was the consensus of the panel that this a between IR and laminitis in horses. in response to insulin the increased synthesis of by endothelial insulin may also promote by the synthesis of and the of the insulin receptor at two different signaling pathways within the vascular endothelial is when the is of the protein kinase to the of IR in humans have been to such that the is the is and may be because of hyperinsulinemia, which results in increased may therefore be in the insulin-resistant as which the of vessels to respond to vascular challenges. the there are no studies on the of EMS although there are a on the of obesity and in of ponies and and ponies and and breeds appear to be more to EMS. the panel that EMS can be management so should be EMS also in other horse including and but is in and and horses require further study to determine the of EMS in these to EMS may be from before and obesity in some horses as as they horses with EMS are between and of when veterinary or are first because of laminitis. A seasonal has been for laminitis in the with the of pasture laminitis and This seasonal in laminitis has been attributed to increased from pasture In the the of pasture laminitis was during the summer and when and were This further evidence to a between and laminitis insulin concentrations and the of insulin of insulin sensitivity measured in ponies predisposed to laminitis suggested a in insulin sensitivity during and this was attributed to changes in pasture suggested that of the EMS phenotype in ponies may be under conditions of lower or dietary but when and effects are of when are produced in excess of the energy of the pasture for growth and they are converted into or such as and EMS can be by a history, a physical of the and should include of the horse for evidence of regional adiposity, including adipose tissue expansion within the neck and body condition for IR the measurement of glucose and insulin concentrations in blood although are to assess insulin sensitivity. important for the future is the development of a panel of to EMS. is detected in horses with EMS because maintain an insulin response in the of blood glucose concentrations are often toward the higher of range of glycemic If is a of diabetes mellitus should be 2 diabetes mellitus in horses and may be more than thought This should be when be attributed to other causes such as stress, of or inflammatory in the absence of factors such as stress, and a feed evidence of IR in horses and ponies. resting insulin concentrations are not to be increased in cases, so the of should also be recognized that in because of in the More research is required to determine cut-off for hyperinsulinemia, but a value of is suggested as a for the of insulin concentrations in normal horses and ponies. conditions are important when the chronic IR associated with EMS. and released as a result of or lower tissue insulin sensitivity and resting glucose and insulin concentrations are likely to be higher in a horse that is currently from laminitis, so should be after the and of this condition has should be collected after an of feed between and These conditions can be by not more than 1 of no than the before Under these hyperinsulinemia evidence of If hyperinsulinemia is not but other components of the EMS phenotype are a of insulin sensitivity should be performed. for of insulin sensitivity is because tissue to insulin may be when glycemic is by A of can be used for this and an for IR in horses has not been to should be under the conditions as blood for resting glucose and insulin be after the and of laminitis has and after an to effects of feed or IV glucose can be to blood glucose and insulin concentrations and determine the and of the resulting under the the of glucose although the and taken for concentrations to to can also be The developed by can also be used to IR in is after to lower blood glucose of the include the required for and information gained about the glycemic and insulinemic A is by first a blood for glucose and insulin and then body weight by insulin These are to of and of insulin for a horse should be into a and then into a before glucose concentrations are measured at and When the is in blood glucose concentrations to the value by so results are available within 1 a is collected at 0 and is for insulin and this the insulin response to be with insulin concentrations at are more insulin than normal and/or the hormone from the circulation at a This is as an of The can be to when used in the but it is to of the so that the horse's response can be for future is a of testing, although this is in the for If clinical signs of and muscle are recognized or blood glucose concentrations of IV and as In to it has been that some other to ponies induces an insulin response in IR These include a type of the 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 require further for diagnostic include the development of a panel of that can be on a blood a panel 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 also be on the is sometimes detected in EMS 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 by the is from the portal blood by the in humans, so hyperinsulinemia can as a result of reduced insulin and/or increased pancreatic concentrations can the of these 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 when these problems are EMS may be from of The EMS phenotype is generally first recognized in is more in although these may Further clinical signs of but not including or of the and skeletal muscle diagnostic results for For example, of an increased hormone in the absence of factors such as and stress, and of the when results in horses and glucose of IR has also been detected in horses with it was the consensus of the panel that normal insulin sensitivity is more in horses with which that the between these conditions is of this questions that require further IR when the was insulin before dysfunction If this is the may IR, but not be the of the If causes IR in some but not is this a of the specific hormones for IR in these the effects of on insulin sensitivity the of the EMS a risk factor for The consensus panel recognized that some equids with EMS so conditions can that horses and ponies with EMS are predisposed to and dysfunction at a in affected Further research is required in this but the panel that equids with EMS be for clinical signs of and for the condition. If is and/or IR, should insulin sensitivity. is for the of in management of EMS involves the amount of energy provided in the diet to induce weight the horse or pony is obese and the of the diet to glycemic and insulinemic responses to the energy of the diet is an important factor in obesity as a contributory factor to EMS. or pasture from the diet is a key component of this because pasture that be horses and ponies should be provided a diet with with should be which can be by a for or by with a and are and are was thought previously that they the of the so they be likely to to the glycemic response after a there is some evidence that there may be and of before they the equine insulin-resistant ponies an insulin response to dietary is therefore that be by and and this value should of when horses or ponies with EMS. can be in for to lower the the amount of a study that results different so this be to the of concentrations in the that is being to a horse or pony with EMS. should be induced in obese horses by the of and by increasing the level of physical In horses that are being of from the diet is sometimes to induce weight obese horse should be on a diet of in an amount to of body weight should be on to that amounts are If an obese horse or pony to weight after has been at an amount to of body weight for this amount should be to amounts should not this of and it should be noted that may lead to of IR, and should be insulin sensitivity has because on pasture can that lead to laminitis in affected horses can to pasture obesity and IR have been but be taken to pasture when the is such as growth in the or for in the of pasture at different of the has that in the is likely to be for horses with IR, after a when accumulate risk factors for include and conditions and of species such as for include in a or with or use of a and ponies with EMS can have of so may be for these insulin-resistant horses that from laminitis be pasture These should be in so that they are to have will not or the diet with a that contains of protein and a of and to the and other in is therefore These are to be in (eg, horses with a overall body condition are to from a dietary because may not energy are available for use in these in which or and/or are in of The energy of these is on so energy and the of IR be taken into before feed is also to the into and to feed as this may the of feed and and in the concentrations of glucose and the energy of the can be increased by or The can be with or with that have been in and are used in equine 1 or of of on energy to 1 of can be or amounts (eg, should be with a over a to of these the is to lower the glycemic and insulinemic response to the which is the to which blood glucose and insulin concentrations in response to the Further information the dietary management of obesity and IR in equids is provided in a physical is an to insulin sensitivity in obese insulin-resistant of of results in a in insulin and in other risk factors (eg, lipid that are for in insulin sensitivity associated with physical activity can in the absence of weight or in fat to the of foot and an in physical activity is for equids with EMS in to promote weight and insulin More research is required to determine an for management of but a is to with 2–3 and/or there should be a in the and of for example, to horses and ponies with EMS can be by the horse's diet, an and or to studies have that IR in is by changes in and diet although these may fail to of of the is to the of management changes to risk factors for laminitis in EMS. used to IR and type 2 diabetes mellitus in humans include insulin and and and insulin and and In and have in the context of management of IR and EMS. can be induced and insulin sensitivity by to is to horses and ponies at a of in the feed for months at the that diet and are ponies and horses are for the horses should be body weight has been by the to for 2 and then for 2 concentrations often range between and in that is being at a supraphysiological clinical signs of such as or have not been observed in of horses with at lower for longer have not been responses to have been in horses and ponies at a of sensitivity by in without the adverse effect of is a that the of insulin within tissues at the postreceptor level likely by protein of and within the appears to be its of with many other and of this first study but studies have not been to in so this be before the is of studies that oral of is lower in horses than therefore be by further of appropriate and are for the management of EMS. was the consensus of the panel that there is evidence to support the use of these at this and that results of studies should be examined before these are in body condition and fat in ponies an on the for Clinical and risk factors for hyperinsulinemia in ponies. and risk factors for hyperinsulinemia in normal horses in of obesity in an equine body condition study. The of Clinical and A study of laminitis in region of the of the by insulin insulin or insulin in and results in association with and in ponies and horses.