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Equine Metabolic Syndrome
S E C T I O N
XIII Endocrine and Metabolic Disease
Equine Metabolic Syndrome
C H A P T E R
135
NICHOLAS FRANK
E
quine metabolic syndrome (EMS) is a collection of endocrine and metabolic abnormalities associated with the development of laminitis in equids. The American College of Veterinary Internal Medicine consensus statement on EMS published in 2010 lists three major components: increased adiposity in specific locations (regional adiposity) or generally (obesity), insulin resistance (IR) with hyper insulinemia, and a predisposition to development of lami nitis. However, laminitis is a consequence of the syndrome and can be avoided if management changes are made. The current definition of EMS focuses on hyperinsulinemia and also includes IR, increased adiposity, hyperleptinemia, and hypertriglyceridemia. The term insulin dysregulation has been introduced to encompass the problems of increased insulin secretion, decreased hepatic insulin clearance, and peripheral IR. Alternative names for EMS include insulin resistance syn drome, peripheral Cushing’s syndrome, and prelaminitic metabolic syndrome. Clinical signs of EMS were attributed to hypothyroidism in the past, but the low resting thyroid hormone concentrations detected in some horses with EMS are better thought of as a consequence, rather than a cause, of obesity.
CLINICAL PRESENTATION
Equine metabolic syndrome can affect all domesticated equids. Pony, Morgan Horses, Paso Finos, and Norwegian Fjord breeds are overrepresented, but the syndrome is recog nized in many other breeds of horse, including Arabians, Quarter Horses, Saddlebreds, Tennessee Walking Horses, and warmbloods. Horses are mature when EMS is first recognized, and the age of onset for laminitis is determined by the con ditions under which the horse has been kept. Genetically predisposed horses that are allowed to become obese and graze on pasture with abundant grass can develop laminitis at a young age, whereas other susceptible horses that are managed appropriately can avoid laminitis altogether. Diver gent growth rings, also called founder lines, are sometimes present on the hoof wall, indicating previous episodes of subclinical laminitis. These protruding growth rings are closer to the coronary band dorsally than they are at the heel, and are thought to occur when laminitis inhibits dorsal hoof wall growth. Physical characteristics of EMS include general ized obesity, regional adiposity, or both. Regional adiposity
takes the form of cresty neck in horses, and neck circum ference has been negatively correlated with insulin sensitiv ity. Other manifestations of regional adiposity include abnormal adipose tissue deposits close to the tailhead, within the prepuce, or randomly distributed beneath the skin (Figure 135-1). Many horses are on pasture when laminitis first develops, and episodes are more common in the spring and fall. Other horses with EMS are first recognized when they present with infertility problems. Colic caused by pedunculated lipomas is a concern in obese equids.
PATHOPHYSIOLOGY
It has long been recognized that EMS is more common in certain breeds of horse, and research is presently being con ducted to examine the genetic basis of this syndrome. If it is assumed that some horses are genetically predisposed to EMS, diet and exercise are two important modifying factors that can affect expression of the phenotype. A genetically predisposed horse that is overfed is more likely to express the EMS phenotype, whereas the same horse might remain healthy if kept in a lean condition, fed appropriately, and exercised regularly. Obesity is an important modifying factor because it can induce IR, and this raises insulin concentra tions. The concept of pathologic fat must also be considered because adipose tissues secrete proinflammatory cytokines as obesity develops. This is accompanied by a shift in adipokine production, with increased leptin secretion and decreased adiponectin production. Detection of high leptin concentra tions confirms that changes in fat metabolism have occurred, and hyperleptinemia is associated with insulin dysregula tion. Hyperinsulinemia and hyperleptinemia might contrib ute to the so-called easy keeper metabolic state recognized in horses with EMS. Insulin dysregulation is a key component of EMS, and postprandial hyperinsulinemia may explain why affected horses grazing on pasture develop laminitis. Laminitis has been experimentally induced in both ponies and Standard bred horses by infusing insulin intravenously at high levels. Postprandial hyperinsulinemia, fasting hyperinsulinemia, and tissue IR occur to varying degrees in horses with EMS, but temporal relationships among these factors require further investigation. One hypothesis is that genetically pre disposed horses first develop postprandial hyperinsulinemia,
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XIII Endocrine and Metabolic Disease recommended for diagnosing IR, but they do not assess the insulin response to ingested sugars, which may be the first manifestation of insulin dysregulation in equids. A CGIT is performed by infusing 50% dextrose solution, immediately followed by intravenous administration of regular insulin, so incretin hormone responses are bypassed. This dynamic test determines the rate of glucose disposal into tissues, which is a measure of insulin sensitivity and the overall insulin response to glucose. The insulin response is also assessed and reflects the rate of insulin secretion from pancreatic beta cells and insulin clearance rate, but does not account for insulin release stimulated by incretin hormones after feeding.
Oral Sugar Test
Figure 135-1 Photograph of a horse with equine metabolic syndrome illustrating the presence of a cresty neck and subcutaneous adipose tissue deposits along the ventrum. (Courtesy of the University of Tennessee.)
and then IR develops over time as the condition progresses. Fasting hyperinsulinemia is the last abnormality to develop as fatty acids stimulate insulin secretion or beta cell hyper plasia develops. Postprandial hyperinsulinemia is a plausible starting point for horses with EMS because high insulin concentrations can induce IR through a process of homolo gous desensitization. This phenomenon is recognized when an insulinoma develops and secretes excessive amounts of insulin. Hyperinsulinemia-induced IR is also a potential mechanism for insulin-induced laminitis. Insulin resistance within endothelial cells would be expected to promote vaso constriction, alter normal blood flow dynamics, and reduce nutrient delivery to laminar tissues. Hyperinsulinemia can develop as a consequence of increased secretion from pancreatic beta cells or slowed clear ance from the blood. Increased insulin secretion following meals might be attributed to altered regulation of incretin hormones; these include glucagon-like peptide 1 and gastro intestinal polypeptide, which are secreted from the small intestine in response to ingested sugars and other nutrients and stimulate the insulin secretion from pancreatic beta cells. Incretin hormones stimulate insulin secretion and slow gastric emptying as glucose concentrations rise after feeding, and this minimizes postprandial hyperglycemia. Both incretin hormones are degraded by the enzyme dipep tidyl transferase-4, so postprandial hyperinsulinemia might result from increased secretion of incretin hormones or slowed degradation. Alterations in incretin hormones could explain the development of postprandial hyperinsulinemia and laminitis in equids grazing on pastures that are rich in simple sugars, starch, and protein.
DIAGNOSTIC TESTING
Diagnostic tests for EMS are summarized (Table 135-1). Rec ommendations for diagnostic testing have shifted recently as greater emphasis has been placed on oral glucose testing. Because insulin concentrations increase after feeding, post prandial hyperinsulinemia is a major concern, particularly when horses are consuming grass on pasture. Equids that are genetically susceptible to postprandial hyperinsulinemia might also be predisposed to obesity and have a higher risk for laminitis. Previous recommendations focused on fasting insulin concentrations and the combined glucoseinsulin test (CGIT). Both remain useful tests and are still
The oral sugar test (OST) was introduced to detect postpran dial hyperinsulinemia and identify horses with a greater risk for laminitis. The OST is performed by administering corn syrup orally and provides a measured dose of glucose that induces transient hyperinsulinemia. Corn syrup is readily available from grocery stores and is easily administered to horses with a dose syringe. An in-feed oral glucose challenge test can be performed as an alternative by mixing dextrose powder (1 g/kg body weight) with water and 1 lb of lownonstructural carbohydrate (NSC) feed and water. A blood sample is collected 2 hours after the horse has completed the meal; postprandial hyperinsulinemia is defined by insulin concentrations higher than 85 µU/mL (mU/L). Both tests can be used to detect postprandial hyperinsulinemia, but the OST is preferred because of the ease of testing and small quantity of glucose administered. Horses do not develop laminitis as a result of the OST, but owners are sometimes reluctant to administer sugars to horses with suspected insulin dysregula tion, so a two-step approach is recommended in these cases. The first step is to measure fasting insulin concentrations because horses with moderate or severe insulin dysregulation would be more likely to develop laminitis, and these animals have high fasting insulin concentrations. If fasting insulin concentrations are within reference range (<20 µU/mL by radioimmunoassay), the OST is performed. This approach is practical considering the heightened awareness of endocri nopathic laminitis, but the second step must be performed to identify mildly affected horses. Another approach to assessing postprandial hyperinsulinemia is to collect two blood samples 30 minutes apart within the 1.5- to 2.5-hour period after feeding.
Endocrine and Metabolic Status Panel Although dynamic tests are more likely to reveal insulin dysregulation, it remains easier to simply collect blood and measure resting hormone and metabolite concentrations. A panel of resting measures is therefore recommended and can be included in annual wellness evaluations for high-risk horses. Horses with a dam or sire affected by EMS and those from breed groups with a higher prevalence of insulin dys regulation are considered high-risk animals. Fasting insulin concentrations should be measured because they increase as tissue insulin sensitivity decreases, and this is referred to as compensated IR. Mechanisms responsible for fasting hyper insulinemia include increased fatty acid flux into pancreatic beta cells, reduced insulin clearance, or beta cell hyperplasia. Conversely, insulin concentrations decrease when beta cell insufficiency develops, and this is accompanied by rising glucose concentrations. This is referred to as uncompensated IR when glucose concentrations remain within reference range and diabetes mellitus when persistent hyperglycemia develops. Beta cell insufficiency occurs at much lower
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TABLE 135-1 Recommended Diagnostic Tests for Equine Metabolic Syndrome
Test
Procedure
Interpretation*
Endocrine and metabolic status panel Fasting required. Leave only one flake Glucose of hay in the stall after 10 PM the Insulin night before and collect blood in Triglycerides the morning. Leptin Collect blood into one EDTA and one ACTH† serum tube.
Oral sugar test (OST) This test is recommended to assess the combined effects of incretin hormones, pancreatic beta cell insulin secretion, and insulin resistance on insulin concentrations. If the owner has concerns about inducing laminitis, a two-step approach is recommended. First, measure fasting insulin concentrations. If within reference range, proceed to the OST. Test meal Insulin concentrations can be measured after feeding to assess postprandial hyperinsulinemia.
Insulin tolerance test (ITT) Hyperinsulinemia can be caused by increased insulin secretion from the pancreatic beta cells and/or insulin resistance. The ITT is used to detect tissue insulin resistance.
Persistent hyperglycemia indicates diabetes mellitus (insulin is normal or increased). Hyperinsulinemia if fasting insulin concentration >20 µU/mL (mU/L). Hypertriglyceridemia if >50 mg/dL; concern if >27 mg/dL. Hyperleptinemia if leptin concentration >4 ng/mL. Refer to PPID (see Chapter 136) for ACTH interpretation.
Fasting required (see above) Owner administers 0.15 mL per kg (approximately 75 mL) Karo Light‡ corn syrup orally with 60-mL catheter-tip syringes. Collect blood 60 and 90 min after administration of corn syrup. Measure glucose and insulin concentrations.
Normal if the insulin concentration is <45 µU/mL at 60 and 90 min. Hyperinsulinemia if the insulin concentration is >60 µU/mL at 60 or 90 min. Equivocal result if the insulin concentration is 45 to 60 µU/mL at 60 or 90 min. Repeat testing at a later time or consider other tests. Excessive glucose response if the glucose concentration is >125 mg/dL at 60 or 90 min.
Owner feeds the horse as normal and contacts the veterinarian when the meal has been consumed. Veterinarian collects two blood samples 30 min apart in the period 90 to 150 min following the meal.
Reference ranges have not been established.
Fasting required (see above) Step 1: Collect a baseline blood sample and inject regular (soluble) insulin§ intravenously at a dosage of 30 mU/kg (0.03 µU/kg). Then collect a second blood sample 30 min after injection. Proceed to step 2 if the glucose concentration has not decreased by 50%. Step 2: Repeat the test on a different day and administer insulin at a dosage of 100 mU/kg (0.10 µU/kg). Feed as normal after the second blood sample.
Horses with normal insulin sensitivity have a 50% decrease within 30 min in response to the 100 mU/kg dose of insulin. If this response is observed with the lower 30 mU/kg dosage, no further testing is required. Hypoglycemia is a concern with this test, and dextrose solution should be kept on hand.
*Cutoff values for assays performed by the Animal Health Diagnostic Laboratory at Cornell University, Ithaca, NY. Insulin and leptin measured by radioimmunoassay and ACTH by chemiluminescent assay. †Recommended for horses > 10 years of age ‡Karo Light, ACH Food Companies, Inc, Cordova, TN. §Humulin-R, Eli Lilly and Company, Indianapolis, IN. ACTH, Adrenocorticotropic hormone; PPID, pituitary pars intermedia dysfunction.
frequency in horses than other animals, and pancreatitis and pituitary pars intermedia dysfunction (PPID) are two impor tant differential diagnoses. Hypertriglyceridemia has been identified as a predictor of laminitis risk in ponies, with cutoff values of 57 and 94 mg/ dL established from two studies involving the same popula tion of animals. A lower cutoff value of 27 mg/dL has been proposed for horses on the basis of the current EMS genetics study, and breed-specific reference ranges may be forthcom ing. Leptin can also be measured, and hyperleptinemia
(>4 ng/mL) indicates that adipose tissues are abnormal and secreting excessive amounts of leptin. Hyperleptinemia is associated with insulin dysregulation. Affected horses should be assessed by performing an OST, even if fasting insulin concentrations are within reference range.
Insulin Resistance Testing The OST provides evidence of IR when this problem is exacerbating hyperinsulinemia because higher glucose and insulin concentrations are detected in insulin-resistant
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horses. However, the specific problem of tissue IR can be further investigated by performing an insulin tolerance test (ITT) or CGIT. The ITT is described (see Table 135-1), and a two-step approach is recommended to allay concerns about inducing hypoglycemia. To perform a CGIT, the horse should be fasted overnight and an intravenous catheter placed to minimize stress associated with multiple blood collections. A preinfusion (baseline) blood sample is collected, and 150 mg/kg body weight of 50% dextrose solution is infused (150 mL for a 500-kg horse), immediately followed by 0.10 units/kg of regular insulin (0.50 mL for a 500-kg horse). Blood samples are collected at 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 120, 135, and 150 minutes after infusion, but these intervals can be adjusted to 0, 15, 30, 45, and 60 minutes in the field. Insulin resistance is defined by the maintenance of blood glucose concentrations (measured with a hand-held glucometer) above baseline for 45 minutes or longer. The area under the insulin concentration curve should also be examined and reflects both the beta cell response and clear ance rate of endogenous and exogenous insulin. Measuring the insulin concentration at 45 minutes provides informa tion about the height of this insulin peak; concentrations greater than 100 µU/mL (by radioimmunoassay) are abnor mal. There is a small risk for hypoglycemia with both the ITT and CGIT, so two 60-mL syringes containing 50% dextrose should be kept on hand and administered if sweating, muscle fasciculations, or weakness is observed, or if blood glucose concentration drops below 40 mg/dL.
housing in a dirt paddock. Each patient should be individu ally assessed before formulating a management plan. A mildly affected horse with EMS that is obese as a result of overfeeding will generally respond well to energy restriction and can be returned to pasture with a muzzle in place. Grazing in the early morning is likely to be safer for horses with insulin dysregulation, except after a hard frost when grasses rapidly accumulate sugars. In contrast, a severely hyperinsulinemic horse that has recently developed lamini tis should remain off pasture until insulin concentrations improve. Responses to management changes should then be reassessed and housing conditions adjusted over time. Horses held off pasture should receive 1000 IU vitamin E per day as a supplement because access to green grass has been restricted. Patients that are laminitic should not be exercised until hoof structures have stabilized, but horses that are sound can be exercised regularly. Exercise recom mendations must be adjusted to the individual horse and owner, but the goals are to increase energy consumption and improve insulin sensitivity. A greater amount of energy is expended when the exercise regimen is strenuous and sus tained, so owners are encouraged to commit time to exercis ing their horse as frequently as possible. Daily exercise for a minimum of 1 hour, with trotting and cantering, work on hillsides, or time on a treadmill, is a goal for weight reduction programs. Even if the horse cannot be exercised at this level, turnout with other horses and walking in hand are recom mended starting points.
MANAGEMENT
DIETARY MANAGEMENT OF HYPERINSULINEMIA
Obesity
Because obesity is an exacerbating factor for insulin dysregu lation in equids, this problem must be addressed. Obesity itself poses additional health risks to the horse, including increased production of inflammatory cytokines, equine hyperlipemia, infertility, and pedunculated lipomas. Weight loss should be induced in obese horses by limiting access to pasture, removing grain from the diet, and feeding hay in amounts equivalent to 1.5% of current body weight (15 lb hay for a 1000-lb horse) per day at maximum. A vitaminmineral supplement should always be provided, and a ration balancer containing additional protein is recommended for horses on hay-only diets. If there is no improvement in body condition after 4 weeks, the amount of hay should be lowered to 1.5% of the ideal body weight per day, and after another 4 weeks without progress, the amount can be lowered to 1.25% of ideal body weight. In obese ponies, it may be neces sary to reduce the amount of hay fed to 1% of body weight, but this is the minimal level recommended. It is preferable to provide feed in smaller amounts more frequently, and automatic feeders can be used to achieve this. The concept of weight loss resistance has been introduced recently and reflects the experiences of many practitioners. Some obese horses and ponies respond well to weight reduction diets and exercise programs, whereas others appear resistant to weight loss. Pasture access should be restricted in horses with EMS because the obese body condition will often be maintained unless grass intake is limited. Recommended strategies for limiting grass consumption include housing the obese horse with a companion in a small grass paddock that is one third to one half of an acre (equivalent to a square with 120- to 150-ft dimensions) in size. Alternatively or in addition, a grazing muzzle can be placed on the horse during turnout. Other methods of limiting grass intake include short (1-hour) turnout periods, strip grazing with an electric fence, or
Hay with low NSC content should be selected if OST insulin concentrations are markedly increased and postprandial hyperinsulinemia is a concern. Nonstructural carbohydrates include simple sugars, starch, and fructans, and the NSC content of the hay is calculated by taking the sum of watersoluble carbohydrate and starch percentages on a dry matter basis. This method of calculating NSC includes fructans, which are less likely to contribute to postprandial insulin emic responses, so an alternative approach is to take the sum of the starch and ethanol-soluble carbohydrate percentages. When this approach is used, hay with NSC content of less than 10% is recommended, although this is not an absolute cutoff value. If it is only possible to acquire hay with margin ally higher NSC content, soaking for 30 to 60 minutes in cold water is recommended to lower the sugar content before feeding. It should be noted, however, that the amount of water-soluble carbohydrate lost through soaking varies con siderably among different batches of hay. Complete feeds and bagged forages are also available for horses with EMS. Feeds that are lower in starches and sugar should be selected, and treats such as sugar cubes should be avoided altogether. Some horses with EMS have a normal or lean body condition and require additional calories. A diet con sisting of hay, pelleted low-NSC feed, balanced vitamin and mineral supplement, and 0.5 cup vegetable oil (equal to 125 mL; contains approximately 100 g fat) twice daily can be recommended in these cases. If the owner cannot afford a commercial low-NSC feed, molasses-free beet pulp can be fed as an alternative, although it should be soaked before feeding to remove simple sugars and lower the risk for esoph ageal obstruction. Recommendations for reducing the incidence of pastureassociated laminitis in genetically susceptible horses include limiting time on pasture or use of a grazing muzzle. These interventions are particularly important when the grass is
green and growing rapidly, first drying out at the beginning of a summer drought, rapidly growing after a heavy summer rain, or entering winter dormancy. Pasture access should be limited when the grass is in any of these dynamic phases.
RELATIONSHIP WITH PITUITARY PARS INTERMEDIA DYSFUNCTION
Relationships between EMS and PPID still remain to be elu cidated. Chronic obesity and insulin dysregulation poten tially increase the risk for PPID in equids, so close monitoring is recommended in these patients. Clinical signs of PPID were observed and pituitary adenomas identified at postmor tem examination in horses with EMS maintained in a longterm research study. Owners should monitor horses with EMS for haircoat changes, loss of muscle mass, and shifts in metabolism. Pituitary pars intermedia dysfunction should be investigated if a horse that previously battled obesity begins looking thinner and requires more energy for maintenance. Skeletal muscle atrophy and generalized hypertrichosis may not be evident initially, but shedding is sometimes delayed for a few weeks, and regional hypertrichosis can be observed. The development of PPID in a horse with underlying insulin dysregulation is significant because hyperadrenocorticism can induce IR and increase insulin concentrations. Higher insulin concentrations increase the risk for laminitis, and this problem is observed in middle-aged horses that develop PPID in addition to EMS. It is therefore important to diag nose and medically manage PPID in horses with a previous diagnosis of EMS.
DRUG THERAPY
There are two indications for pharmacologic intervention in the management of insulin dysregulation. Levothyroxine can be administered to accelerate weight loss in obese animals, and metformin can be prescribed to manage post prandial hyperinsulinemia.
Levothyroxine Sodium Levothyroxine accelerates weight loss in horses that are placed on a controlled diet, and this is accompanied by increased insulin sensitivity. This approach should be reserved for obese horses and only those with high insulin concentrations or weight loss resistance. In a research study, pretreatment with levothyroxine for 14 days prevented healthy horses from developing IR following endotoxin infusion. Levothyroxine is administered at an initial dosage of 0.1 mg/kg once daily by mouth, which is rounded to 48 mg/day (4 teaspoons/day) for horses weighing 450 to 525 kg. A higher dosage of 0.15 mg/kg has been selected for horses that do not start to lose weight after 1 month. A mild state of hyperthyroidism is induced, and treatment at the dosages recommended previously should only extend for 3 to 6 months. Ongoing supplementation of horses with levothyroxine at lower dosages is common practice
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and unlikely to be harmful, but has not been supported by research.
Metformin Hydrochloride Because the oral bioavailability of generic metformin tablets is low (approximately 7% in fasted horses), it has been ques tioned whether the well-established effects of this drug on insulin sensitivity occur in horses. Additional information was recently provided to resolve this question when it was demonstrated that metformin (30 mg/kg) given orally 30 minutes before an oral glucose tolerance test significantly lowered glucose and insulin concentrations. These findings suggest that metformin acts at the level of the intestine to limit postprandial hyperinsulinemia, even when its effects on insulin sensitivity are weak. The current recommendation is therefore to administer metformin at a dosage of 30 mg/ kg, given 30 to 60 minutes before feeding, up to 3 times daily. Metformin is available as 1-g tablets and can induce oral cavity irritation in some horses.
Suggested Readings Argo CM, Curtis GC, Grove-White D, et al. Weight loss resistance: a further consideration for the nutritional management of obese Equidae. Vet J 2012;194:179-188. Bertin FR, Sojka-Kritchevsky JE. Comparison of a 2-step insulin-response test to conventional insulin-sensitivity testing in horses. Domest Anim Endocrinol 2012. Carter RA, Treiber KH, Geor RJ, et al. Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies. Equine Vet J 2009;41:171-178. Durham AE, Hughes KJ, Cottle HJ, et al. Type 2 diabetes mellitus with pancreatic beta cell dysfunction in 3 horses confirmed with minimal model analysis. Equine Vet J 2009;41: 924-929. Durham AE, Rendle DI, Rutledge F, et al. The effects of metformin hydrochloride on intestinal glucose absorption and use of tests for hyperinsulinaemia. In: Proceedings of the ACVIM Forum. New Orleans, 2012. Available at: www.vin.com Hustace JL, Firshman AM, Mata JE. Pharmacokinetics and bioavailability of metformin in horses. Am J Vet Res 2009;70: 665-668. Longland AC, Barfoot C, Harris PA. Effects of soaking on the water-soluble carbohydrate and crude protein content of hay. Vet Rec 2011;168:618. Thatcher CD, Pleasant RS, Geor RJ, et al. Prevalence of overconditioning in mature horses in Southwest Virginia during the summer. J Vet Intern Med 2012;26:1413-1418. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies. J Am Vet Med Assoc 2006;228:1538-1545. Vick MM, Adams AA, Murphy BA, et al. Relationships among inflammatory cytokines, obesity, and insulin sensitivity in the horse. J Anim Sci 2007;85:1144-1155.
XIII Endocrine and Metabolic Disease
Equine Metabolic Syndrome
C H A P T E R
135
NICHOLAS FRANK
E
quine metabolic syndrome (EMS) is a collection of endocrine and metabolic abnormalities associated with the development of laminitis in equids. The American College of Veterinary Internal Medicine consensus statement on EMS published in 2010 lists three major components: increased adiposity in specific locations (regional adiposity) or generally (obesity), insulin resistance (IR) with hyper insulinemia, and a predisposition to development of lami nitis. However, laminitis is a consequence of the syndrome and can be avoided if management changes are made. The current definition of EMS focuses on hyperinsulinemia and also includes IR, increased adiposity, hyperleptinemia, and hypertriglyceridemia. The term insulin dysregulation has been introduced to encompass the problems of increased insulin secretion, decreased hepatic insulin clearance, and peripheral IR. Alternative names for EMS include insulin resistance syn drome, peripheral Cushing’s syndrome, and prelaminitic metabolic syndrome. Clinical signs of EMS were attributed to hypothyroidism in the past, but the low resting thyroid hormone concentrations detected in some horses with EMS are better thought of as a consequence, rather than a cause, of obesity.
CLINICAL PRESENTATION
Equine metabolic syndrome can affect all domesticated equids. Pony, Morgan Horses, Paso Finos, and Norwegian Fjord breeds are overrepresented, but the syndrome is recog nized in many other breeds of horse, including Arabians, Quarter Horses, Saddlebreds, Tennessee Walking Horses, and warmbloods. Horses are mature when EMS is first recognized, and the age of onset for laminitis is determined by the con ditions under which the horse has been kept. Genetically predisposed horses that are allowed to become obese and graze on pasture with abundant grass can develop laminitis at a young age, whereas other susceptible horses that are managed appropriately can avoid laminitis altogether. Diver gent growth rings, also called founder lines, are sometimes present on the hoof wall, indicating previous episodes of subclinical laminitis. These protruding growth rings are closer to the coronary band dorsally than they are at the heel, and are thought to occur when laminitis inhibits dorsal hoof wall growth. Physical characteristics of EMS include general ized obesity, regional adiposity, or both. Regional adiposity
takes the form of cresty neck in horses, and neck circum ference has been negatively correlated with insulin sensitiv ity. Other manifestations of regional adiposity include abnormal adipose tissue deposits close to the tailhead, within the prepuce, or randomly distributed beneath the skin (Figure 135-1). Many horses are on pasture when laminitis first develops, and episodes are more common in the spring and fall. Other horses with EMS are first recognized when they present with infertility problems. Colic caused by pedunculated lipomas is a concern in obese equids.
PATHOPHYSIOLOGY
It has long been recognized that EMS is more common in certain breeds of horse, and research is presently being con ducted to examine the genetic basis of this syndrome. If it is assumed that some horses are genetically predisposed to EMS, diet and exercise are two important modifying factors that can affect expression of the phenotype. A genetically predisposed horse that is overfed is more likely to express the EMS phenotype, whereas the same horse might remain healthy if kept in a lean condition, fed appropriately, and exercised regularly. Obesity is an important modifying factor because it can induce IR, and this raises insulin concentra tions. The concept of pathologic fat must also be considered because adipose tissues secrete proinflammatory cytokines as obesity develops. This is accompanied by a shift in adipokine production, with increased leptin secretion and decreased adiponectin production. Detection of high leptin concentra tions confirms that changes in fat metabolism have occurred, and hyperleptinemia is associated with insulin dysregula tion. Hyperinsulinemia and hyperleptinemia might contrib ute to the so-called easy keeper metabolic state recognized in horses with EMS. Insulin dysregulation is a key component of EMS, and postprandial hyperinsulinemia may explain why affected horses grazing on pasture develop laminitis. Laminitis has been experimentally induced in both ponies and Standard bred horses by infusing insulin intravenously at high levels. Postprandial hyperinsulinemia, fasting hyperinsulinemia, and tissue IR occur to varying degrees in horses with EMS, but temporal relationships among these factors require further investigation. One hypothesis is that genetically pre disposed horses first develop postprandial hyperinsulinemia,
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XIII Endocrine and Metabolic Disease recommended for diagnosing IR, but they do not assess the insulin response to ingested sugars, which may be the first manifestation of insulin dysregulation in equids. A CGIT is performed by infusing 50% dextrose solution, immediately followed by intravenous administration of regular insulin, so incretin hormone responses are bypassed. This dynamic test determines the rate of glucose disposal into tissues, which is a measure of insulin sensitivity and the overall insulin response to glucose. The insulin response is also assessed and reflects the rate of insulin secretion from pancreatic beta cells and insulin clearance rate, but does not account for insulin release stimulated by incretin hormones after feeding.
Oral Sugar Test
Figure 135-1 Photograph of a horse with equine metabolic syndrome illustrating the presence of a cresty neck and subcutaneous adipose tissue deposits along the ventrum. (Courtesy of the University of Tennessee.)
and then IR develops over time as the condition progresses. Fasting hyperinsulinemia is the last abnormality to develop as fatty acids stimulate insulin secretion or beta cell hyper plasia develops. Postprandial hyperinsulinemia is a plausible starting point for horses with EMS because high insulin concentrations can induce IR through a process of homolo gous desensitization. This phenomenon is recognized when an insulinoma develops and secretes excessive amounts of insulin. Hyperinsulinemia-induced IR is also a potential mechanism for insulin-induced laminitis. Insulin resistance within endothelial cells would be expected to promote vaso constriction, alter normal blood flow dynamics, and reduce nutrient delivery to laminar tissues. Hyperinsulinemia can develop as a consequence of increased secretion from pancreatic beta cells or slowed clear ance from the blood. Increased insulin secretion following meals might be attributed to altered regulation of incretin hormones; these include glucagon-like peptide 1 and gastro intestinal polypeptide, which are secreted from the small intestine in response to ingested sugars and other nutrients and stimulate the insulin secretion from pancreatic beta cells. Incretin hormones stimulate insulin secretion and slow gastric emptying as glucose concentrations rise after feeding, and this minimizes postprandial hyperglycemia. Both incretin hormones are degraded by the enzyme dipep tidyl transferase-4, so postprandial hyperinsulinemia might result from increased secretion of incretin hormones or slowed degradation. Alterations in incretin hormones could explain the development of postprandial hyperinsulinemia and laminitis in equids grazing on pastures that are rich in simple sugars, starch, and protein.
DIAGNOSTIC TESTING
Diagnostic tests for EMS are summarized (Table 135-1). Rec ommendations for diagnostic testing have shifted recently as greater emphasis has been placed on oral glucose testing. Because insulin concentrations increase after feeding, post prandial hyperinsulinemia is a major concern, particularly when horses are consuming grass on pasture. Equids that are genetically susceptible to postprandial hyperinsulinemia might also be predisposed to obesity and have a higher risk for laminitis. Previous recommendations focused on fasting insulin concentrations and the combined glucoseinsulin test (CGIT). Both remain useful tests and are still
The oral sugar test (OST) was introduced to detect postpran dial hyperinsulinemia and identify horses with a greater risk for laminitis. The OST is performed by administering corn syrup orally and provides a measured dose of glucose that induces transient hyperinsulinemia. Corn syrup is readily available from grocery stores and is easily administered to horses with a dose syringe. An in-feed oral glucose challenge test can be performed as an alternative by mixing dextrose powder (1 g/kg body weight) with water and 1 lb of lownonstructural carbohydrate (NSC) feed and water. A blood sample is collected 2 hours after the horse has completed the meal; postprandial hyperinsulinemia is defined by insulin concentrations higher than 85 µU/mL (mU/L). Both tests can be used to detect postprandial hyperinsulinemia, but the OST is preferred because of the ease of testing and small quantity of glucose administered. Horses do not develop laminitis as a result of the OST, but owners are sometimes reluctant to administer sugars to horses with suspected insulin dysregula tion, so a two-step approach is recommended in these cases. The first step is to measure fasting insulin concentrations because horses with moderate or severe insulin dysregulation would be more likely to develop laminitis, and these animals have high fasting insulin concentrations. If fasting insulin concentrations are within reference range (<20 µU/mL by radioimmunoassay), the OST is performed. This approach is practical considering the heightened awareness of endocri nopathic laminitis, but the second step must be performed to identify mildly affected horses. Another approach to assessing postprandial hyperinsulinemia is to collect two blood samples 30 minutes apart within the 1.5- to 2.5-hour period after feeding.
Endocrine and Metabolic Status Panel Although dynamic tests are more likely to reveal insulin dysregulation, it remains easier to simply collect blood and measure resting hormone and metabolite concentrations. A panel of resting measures is therefore recommended and can be included in annual wellness evaluations for high-risk horses. Horses with a dam or sire affected by EMS and those from breed groups with a higher prevalence of insulin dys regulation are considered high-risk animals. Fasting insulin concentrations should be measured because they increase as tissue insulin sensitivity decreases, and this is referred to as compensated IR. Mechanisms responsible for fasting hyper insulinemia include increased fatty acid flux into pancreatic beta cells, reduced insulin clearance, or beta cell hyperplasia. Conversely, insulin concentrations decrease when beta cell insufficiency develops, and this is accompanied by rising glucose concentrations. This is referred to as uncompensated IR when glucose concentrations remain within reference range and diabetes mellitus when persistent hyperglycemia develops. Beta cell insufficiency occurs at much lower
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TABLE 135-1 Recommended Diagnostic Tests for Equine Metabolic Syndrome
Test
Procedure
Interpretation*
Endocrine and metabolic status panel Fasting required. Leave only one flake Glucose of hay in the stall after 10 PM the Insulin night before and collect blood in Triglycerides the morning. Leptin Collect blood into one EDTA and one ACTH† serum tube.
Oral sugar test (OST) This test is recommended to assess the combined effects of incretin hormones, pancreatic beta cell insulin secretion, and insulin resistance on insulin concentrations. If the owner has concerns about inducing laminitis, a two-step approach is recommended. First, measure fasting insulin concentrations. If within reference range, proceed to the OST. Test meal Insulin concentrations can be measured after feeding to assess postprandial hyperinsulinemia.
Insulin tolerance test (ITT) Hyperinsulinemia can be caused by increased insulin secretion from the pancreatic beta cells and/or insulin resistance. The ITT is used to detect tissue insulin resistance.
Persistent hyperglycemia indicates diabetes mellitus (insulin is normal or increased). Hyperinsulinemia if fasting insulin concentration >20 µU/mL (mU/L). Hypertriglyceridemia if >50 mg/dL; concern if >27 mg/dL. Hyperleptinemia if leptin concentration >4 ng/mL. Refer to PPID (see Chapter 136) for ACTH interpretation.
Fasting required (see above) Owner administers 0.15 mL per kg (approximately 75 mL) Karo Light‡ corn syrup orally with 60-mL catheter-tip syringes. Collect blood 60 and 90 min after administration of corn syrup. Measure glucose and insulin concentrations.
Normal if the insulin concentration is <45 µU/mL at 60 and 90 min. Hyperinsulinemia if the insulin concentration is >60 µU/mL at 60 or 90 min. Equivocal result if the insulin concentration is 45 to 60 µU/mL at 60 or 90 min. Repeat testing at a later time or consider other tests. Excessive glucose response if the glucose concentration is >125 mg/dL at 60 or 90 min.
Owner feeds the horse as normal and contacts the veterinarian when the meal has been consumed. Veterinarian collects two blood samples 30 min apart in the period 90 to 150 min following the meal.
Reference ranges have not been established.
Fasting required (see above) Step 1: Collect a baseline blood sample and inject regular (soluble) insulin§ intravenously at a dosage of 30 mU/kg (0.03 µU/kg). Then collect a second blood sample 30 min after injection. Proceed to step 2 if the glucose concentration has not decreased by 50%. Step 2: Repeat the test on a different day and administer insulin at a dosage of 100 mU/kg (0.10 µU/kg). Feed as normal after the second blood sample.
Horses with normal insulin sensitivity have a 50% decrease within 30 min in response to the 100 mU/kg dose of insulin. If this response is observed with the lower 30 mU/kg dosage, no further testing is required. Hypoglycemia is a concern with this test, and dextrose solution should be kept on hand.
*Cutoff values for assays performed by the Animal Health Diagnostic Laboratory at Cornell University, Ithaca, NY. Insulin and leptin measured by radioimmunoassay and ACTH by chemiluminescent assay. †Recommended for horses > 10 years of age ‡Karo Light, ACH Food Companies, Inc, Cordova, TN. §Humulin-R, Eli Lilly and Company, Indianapolis, IN. ACTH, Adrenocorticotropic hormone; PPID, pituitary pars intermedia dysfunction.
frequency in horses than other animals, and pancreatitis and pituitary pars intermedia dysfunction (PPID) are two impor tant differential diagnoses. Hypertriglyceridemia has been identified as a predictor of laminitis risk in ponies, with cutoff values of 57 and 94 mg/ dL established from two studies involving the same popula tion of animals. A lower cutoff value of 27 mg/dL has been proposed for horses on the basis of the current EMS genetics study, and breed-specific reference ranges may be forthcom ing. Leptin can also be measured, and hyperleptinemia
(>4 ng/mL) indicates that adipose tissues are abnormal and secreting excessive amounts of leptin. Hyperleptinemia is associated with insulin dysregulation. Affected horses should be assessed by performing an OST, even if fasting insulin concentrations are within reference range.
Insulin Resistance Testing The OST provides evidence of IR when this problem is exacerbating hyperinsulinemia because higher glucose and insulin concentrations are detected in insulin-resistant
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horses. However, the specific problem of tissue IR can be further investigated by performing an insulin tolerance test (ITT) or CGIT. The ITT is described (see Table 135-1), and a two-step approach is recommended to allay concerns about inducing hypoglycemia. To perform a CGIT, the horse should be fasted overnight and an intravenous catheter placed to minimize stress associated with multiple blood collections. A preinfusion (baseline) blood sample is collected, and 150 mg/kg body weight of 50% dextrose solution is infused (150 mL for a 500-kg horse), immediately followed by 0.10 units/kg of regular insulin (0.50 mL for a 500-kg horse). Blood samples are collected at 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 120, 135, and 150 minutes after infusion, but these intervals can be adjusted to 0, 15, 30, 45, and 60 minutes in the field. Insulin resistance is defined by the maintenance of blood glucose concentrations (measured with a hand-held glucometer) above baseline for 45 minutes or longer. The area under the insulin concentration curve should also be examined and reflects both the beta cell response and clear ance rate of endogenous and exogenous insulin. Measuring the insulin concentration at 45 minutes provides informa tion about the height of this insulin peak; concentrations greater than 100 µU/mL (by radioimmunoassay) are abnor mal. There is a small risk for hypoglycemia with both the ITT and CGIT, so two 60-mL syringes containing 50% dextrose should be kept on hand and administered if sweating, muscle fasciculations, or weakness is observed, or if blood glucose concentration drops below 40 mg/dL.
housing in a dirt paddock. Each patient should be individu ally assessed before formulating a management plan. A mildly affected horse with EMS that is obese as a result of overfeeding will generally respond well to energy restriction and can be returned to pasture with a muzzle in place. Grazing in the early morning is likely to be safer for horses with insulin dysregulation, except after a hard frost when grasses rapidly accumulate sugars. In contrast, a severely hyperinsulinemic horse that has recently developed lamini tis should remain off pasture until insulin concentrations improve. Responses to management changes should then be reassessed and housing conditions adjusted over time. Horses held off pasture should receive 1000 IU vitamin E per day as a supplement because access to green grass has been restricted. Patients that are laminitic should not be exercised until hoof structures have stabilized, but horses that are sound can be exercised regularly. Exercise recom mendations must be adjusted to the individual horse and owner, but the goals are to increase energy consumption and improve insulin sensitivity. A greater amount of energy is expended when the exercise regimen is strenuous and sus tained, so owners are encouraged to commit time to exercis ing their horse as frequently as possible. Daily exercise for a minimum of 1 hour, with trotting and cantering, work on hillsides, or time on a treadmill, is a goal for weight reduction programs. Even if the horse cannot be exercised at this level, turnout with other horses and walking in hand are recom mended starting points.
MANAGEMENT
DIETARY MANAGEMENT OF HYPERINSULINEMIA
Obesity
Because obesity is an exacerbating factor for insulin dysregu lation in equids, this problem must be addressed. Obesity itself poses additional health risks to the horse, including increased production of inflammatory cytokines, equine hyperlipemia, infertility, and pedunculated lipomas. Weight loss should be induced in obese horses by limiting access to pasture, removing grain from the diet, and feeding hay in amounts equivalent to 1.5% of current body weight (15 lb hay for a 1000-lb horse) per day at maximum. A vitaminmineral supplement should always be provided, and a ration balancer containing additional protein is recommended for horses on hay-only diets. If there is no improvement in body condition after 4 weeks, the amount of hay should be lowered to 1.5% of the ideal body weight per day, and after another 4 weeks without progress, the amount can be lowered to 1.25% of ideal body weight. In obese ponies, it may be neces sary to reduce the amount of hay fed to 1% of body weight, but this is the minimal level recommended. It is preferable to provide feed in smaller amounts more frequently, and automatic feeders can be used to achieve this. The concept of weight loss resistance has been introduced recently and reflects the experiences of many practitioners. Some obese horses and ponies respond well to weight reduction diets and exercise programs, whereas others appear resistant to weight loss. Pasture access should be restricted in horses with EMS because the obese body condition will often be maintained unless grass intake is limited. Recommended strategies for limiting grass consumption include housing the obese horse with a companion in a small grass paddock that is one third to one half of an acre (equivalent to a square with 120- to 150-ft dimensions) in size. Alternatively or in addition, a grazing muzzle can be placed on the horse during turnout. Other methods of limiting grass intake include short (1-hour) turnout periods, strip grazing with an electric fence, or
Hay with low NSC content should be selected if OST insulin concentrations are markedly increased and postprandial hyperinsulinemia is a concern. Nonstructural carbohydrates include simple sugars, starch, and fructans, and the NSC content of the hay is calculated by taking the sum of watersoluble carbohydrate and starch percentages on a dry matter basis. This method of calculating NSC includes fructans, which are less likely to contribute to postprandial insulin emic responses, so an alternative approach is to take the sum of the starch and ethanol-soluble carbohydrate percentages. When this approach is used, hay with NSC content of less than 10% is recommended, although this is not an absolute cutoff value. If it is only possible to acquire hay with margin ally higher NSC content, soaking for 30 to 60 minutes in cold water is recommended to lower the sugar content before feeding. It should be noted, however, that the amount of water-soluble carbohydrate lost through soaking varies con siderably among different batches of hay. Complete feeds and bagged forages are also available for horses with EMS. Feeds that are lower in starches and sugar should be selected, and treats such as sugar cubes should be avoided altogether. Some horses with EMS have a normal or lean body condition and require additional calories. A diet con sisting of hay, pelleted low-NSC feed, balanced vitamin and mineral supplement, and 0.5 cup vegetable oil (equal to 125 mL; contains approximately 100 g fat) twice daily can be recommended in these cases. If the owner cannot afford a commercial low-NSC feed, molasses-free beet pulp can be fed as an alternative, although it should be soaked before feeding to remove simple sugars and lower the risk for esoph ageal obstruction. Recommendations for reducing the incidence of pastureassociated laminitis in genetically susceptible horses include limiting time on pasture or use of a grazing muzzle. These interventions are particularly important when the grass is
green and growing rapidly, first drying out at the beginning of a summer drought, rapidly growing after a heavy summer rain, or entering winter dormancy. Pasture access should be limited when the grass is in any of these dynamic phases.
RELATIONSHIP WITH PITUITARY PARS INTERMEDIA DYSFUNCTION
Relationships between EMS and PPID still remain to be elu cidated. Chronic obesity and insulin dysregulation poten tially increase the risk for PPID in equids, so close monitoring is recommended in these patients. Clinical signs of PPID were observed and pituitary adenomas identified at postmor tem examination in horses with EMS maintained in a longterm research study. Owners should monitor horses with EMS for haircoat changes, loss of muscle mass, and shifts in metabolism. Pituitary pars intermedia dysfunction should be investigated if a horse that previously battled obesity begins looking thinner and requires more energy for maintenance. Skeletal muscle atrophy and generalized hypertrichosis may not be evident initially, but shedding is sometimes delayed for a few weeks, and regional hypertrichosis can be observed. The development of PPID in a horse with underlying insulin dysregulation is significant because hyperadrenocorticism can induce IR and increase insulin concentrations. Higher insulin concentrations increase the risk for laminitis, and this problem is observed in middle-aged horses that develop PPID in addition to EMS. It is therefore important to diag nose and medically manage PPID in horses with a previous diagnosis of EMS.
DRUG THERAPY
There are two indications for pharmacologic intervention in the management of insulin dysregulation. Levothyroxine can be administered to accelerate weight loss in obese animals, and metformin can be prescribed to manage post prandial hyperinsulinemia.
Levothyroxine Sodium Levothyroxine accelerates weight loss in horses that are placed on a controlled diet, and this is accompanied by increased insulin sensitivity. This approach should be reserved for obese horses and only those with high insulin concentrations or weight loss resistance. In a research study, pretreatment with levothyroxine for 14 days prevented healthy horses from developing IR following endotoxin infusion. Levothyroxine is administered at an initial dosage of 0.1 mg/kg once daily by mouth, which is rounded to 48 mg/day (4 teaspoons/day) for horses weighing 450 to 525 kg. A higher dosage of 0.15 mg/kg has been selected for horses that do not start to lose weight after 1 month. A mild state of hyperthyroidism is induced, and treatment at the dosages recommended previously should only extend for 3 to 6 months. Ongoing supplementation of horses with levothyroxine at lower dosages is common practice
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and unlikely to be harmful, but has not been supported by research.
Metformin Hydrochloride Because the oral bioavailability of generic metformin tablets is low (approximately 7% in fasted horses), it has been ques tioned whether the well-established effects of this drug on insulin sensitivity occur in horses. Additional information was recently provided to resolve this question when it was demonstrated that metformin (30 mg/kg) given orally 30 minutes before an oral glucose tolerance test significantly lowered glucose and insulin concentrations. These findings suggest that metformin acts at the level of the intestine to limit postprandial hyperinsulinemia, even when its effects on insulin sensitivity are weak. The current recommendation is therefore to administer metformin at a dosage of 30 mg/ kg, given 30 to 60 minutes before feeding, up to 3 times daily. Metformin is available as 1-g tablets and can induce oral cavity irritation in some horses.
Suggested Readings Argo CM, Curtis GC, Grove-White D, et al. Weight loss resistance: a further consideration for the nutritional management of obese Equidae. Vet J 2012;194:179-188. Bertin FR, Sojka-Kritchevsky JE. Comparison of a 2-step insulin-response test to conventional insulin-sensitivity testing in horses. Domest Anim Endocrinol 2012. Carter RA, Treiber KH, Geor RJ, et al. Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies. Equine Vet J 2009;41:171-178. Durham AE, Hughes KJ, Cottle HJ, et al. Type 2 diabetes mellitus with pancreatic beta cell dysfunction in 3 horses confirmed with minimal model analysis. Equine Vet J 2009;41: 924-929. Durham AE, Rendle DI, Rutledge F, et al. The effects of metformin hydrochloride on intestinal glucose absorption and use of tests for hyperinsulinaemia. In: Proceedings of the ACVIM Forum. New Orleans, 2012. Available at: www.vin.com Hustace JL, Firshman AM, Mata JE. Pharmacokinetics and bioavailability of metformin in horses. Am J Vet Res 2009;70: 665-668. Longland AC, Barfoot C, Harris PA. Effects of soaking on the water-soluble carbohydrate and crude protein content of hay. Vet Rec 2011;168:618. Thatcher CD, Pleasant RS, Geor RJ, et al. Prevalence of overconditioning in mature horses in Southwest Virginia during the summer. J Vet Intern Med 2012;26:1413-1418. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies. J Am Vet Med Assoc 2006;228:1538-1545. Vick MM, Adams AA, Murphy BA, et al. Relationships among inflammatory cytokines, obesity, and insulin sensitivity in the horse. J Anim Sci 2007;85:1144-1155.