Equine Metabolic Syndrome

Introduction

In the past decade a condition has been recognized with increasing frequency called equine metabolic syndrome (EMS), or peripheral Cushing’s disease.  This is a condition that previously has been suspected to be a manifestation of hypothyroidism, but as we now know this condition is unrelated to thyroid dysfunction.  These horses are typically obese in body condition and capable of surviving on minimal caloric intake.  The terminology comes from a similar condition that has been reported in people called omental Cushing’s disease, named after the tissue where adiposity predominates. 

 

Clinical Disease

Clinically affected horses range in age from 6 to 20 years, but rarely are these horses presented initially as geriatric horses, unless undiagnosed until this time.  Breed predilection has been observed and has been reported for some pony breeds, domesticated Spanish mustangs, Peruvian Pasos, Paso Finos, European Warmbloods, American Saddlebreds, and Morgan Horses.  One common similarity among affected horses is a tendency for obesity; specific locations of fat deposition include crest of the neck, over the gluteal region, and in geldings commonly the prepuce is quite thickened with adipose tissue.  Affected female horses are noted for their difficulty in being successfully bred and demonstrate abnormal ovarian cycling activity.  Managers of affected horses describe these horses to “live on air” and in many cases this is despite a significant effort implemented to try to improve the horses’ body condition.  Upon examination of these horses, either with an ultrasound or during exploration of the peritoneal cavity significant intraabdominal fat is observed.  In many cases, the presenting complaint includes a history of laminitis, many clinicians have observed the strong association between the development of laminitis in horses with EMS.  Although initial examination may represent the first time that the horse owner has identified a major problem, many horses on physical and radiologic examination of the distal phalanx will have evidence of chronic laminitis.  However, in other settings EMS is not the presenting complaint, instead the horse has been presented to the clinician for routine health care and it is observed that the horse is not in appropriate body condition.  In such cases, evidence for chronic laminitis is commonly apparent, represented by abnormal growth rings on the hoof wall and dropped sole on closer inspection of the hoof.  Hematologic abnormalities are uncommon on examination of horses with EMS +/-laminitis unless pain and stress are severe.  Slight to moderate hyperglycemia and elevated triglycerides might be identified in some individuals with EMS.        

 

Diagnostic Testing

Horses affected with EMS consistently demonstrate elevated fasting (5 hour) serum insulin levels (>300 pmol/L).  Subsequently, and similar to the human condition, terminology for the disease has sometimes been termed “hyperinsulinemic syndrome”.  Insensitivity to insulin represents one of the most important underlying aspects of the pathogenesis of EMS and this is why some investigators feel that affected horses are under the influence of a state of an “insulin-counter-regulatory overdrive”.  Many hormonal influences act together to result in a condition of insulin resistance, hypertension, and dyslipidemia.  Although it remains unknown to what effect hypertension and dyslipidemia are involved in the equine manifestation of disease, clearly insulin resistance is present and quite pronounced in some individuals.  Since the equine diet is typically extremely low in fat content (<2%) when compared with human diets, the role of fat in the pathogenesis of equine disease remains undetermined.  The effectiveness of insulin in the individual patient can be assayed through the use of the intravenous glucose tolerance test (IVGTT). 

 

Other Hormones

Blood cortisol concentration is not elevated in metabolic syndrome and dexamethasone suppression testing is normal in affected horses.  Of particular importance is the fact that although T3 and T4 values might be mildly reduced, this is not a condition of poor thyroid function.  Confirmation of adequate thyroid function can be observed in suspect cases following TSH or TRH stimulation, which are the only way to accurately evaluate appropriate thyroid function.  Also important to consider is the fact that in cases of experimental thyroidectomy the condition does not render horses overweight, infertile and suffering from laminitis.  In contrast, these horses demonstrate poor weight gain, ill thrift and a poor hair coat. 

Definitive diagnosis of EMS requires the previously mentioned physical characteristics (obesity, excessive fat deposition, +/- laminitis) in a mature horse.  Supportive evidence for the condition includes hyperinsulinemia and glucose intolerance using an IVGTT.  When other differential diagnoses exist additional diagnostic testing might include dexamethasone suppression testing or thyroid function analysis.

 

Pathology of EMS

Although incompletely understood, obesity remains one of the most important features of disease in affected people and horses.  Clearly an associated genetic component exists, but as of yet, this defect has not been identified.  The obesity that these horses develop is thought to directly relate to the insulin resistant state.  Some adipocytes are not only sites of fat storage, but also highly metabolically active in terms of hormone production.  One hormone that has been identified in people is called resistin; this protein significantly contributes to insulin resistance.  Whether this protein is produced in horses (equine adipocytes) has yet to be identified, but based on the similarity in conditions with people it is highly suspected to be present. 

The overall development of obesity is directly related to the individual intake of calories and energy output.  However, in situations of glucocorticoid (GC) excess the adipocytes that are metabolically active and produce hormones appear to be selectively upregulated.  For example individuals with elevated circulating cortisol levels (stress, pituitary dysfunction), demonstrate increased omental and subcutaneous fat deposition.  Although the exact mechanism of stimulation by GC remains speculative, it is believed that GC might stimulate latent adipocyte progenitors to become hormone producing adipocytes, leading to a cycle of GC induced adipocyte production.  A central focus on the pathogenesis of this condition appears to be the presence of excessive numbers of adipocytes or a relative increase in activity of these cells (secondary to chronic stress), the final result is the adipocyte-controlled insulin insensitivity.

 

Insulin Resistance and Horses?

Although investigated most thoroughly in people, complete understanding of insulin resistance has yet to be achieved in either horses or in people.  The complications that have been commonly recognized in people include a increased risk for development of type-2 diabetes mellitus, hypertension, atherosclerosis, and cardiovascular disease.  The downstream events that may occur in such individuals include myocardial infarction, peripheral neuropathies, nephropathies and retinopathies.  Insulin resistance leads to type-2 diabetes only if the pancreas is unable to accommodate the increased need for insulin production.  Although most obese people and horses are insulin resistant, relatively few will develop overt diabetes.  The condition of overt diabetes in horses (severe hyperglycemia and inappropriately low insulin) is extremely rare, this is thought to be due to the fact that horses have a low fat diet and that horses have a much shorter lifespan when compared to people.  Nonetheless, other tissues that are not dependent on insulin for glucose uptake are exposed to very high levels of glucose during episodes of insulin resistance.  Of these tissues endothelial cells are extremely sensitive to the effects of hyperglycemia, sometimes.   Substantial evidence has demonstrated a central and critical role for endothelial dysfunction in the pathogenesis of vascular complications attributable to insulin insensitivity.  Specifically, increased glucose leads to an overall reduction in endothelial-derived nitric oxide (NO) production and increased expression of endothelin-1 (ET-1) expression.  In combination reduced NO and increased ET-1 leads to a state of overall vasospasticity because NO and ET-1 represent the most potent endothelial relaxing (dilating) and vasoconstricting factors, respectively. 

Endothelial cells are responsible for the coordination of a vast array of molecular signals that control vascular smooth muscle tone.  Under conditions of vasospasticity, induced by conditions of hyperglycemia, dysregulated vascular perfusion, particularly associated with microvascular blood flow may occur.   Although still under investigation, it appears that during periods of endothelial dysfunction, oxygen-derived free radicals are produced and contribute to the condition of vascular dysfunction.  Under conditions of hyperglycemia, elevated endothelial NOsynthase leads to increased NO production, although this might appear beneficial, unfortunately rapid inactivation of NO by powerful oxidants results in an overall reduced activity of NO.  During this process the inflammatory cascade of cyclooxygenase is induced.  Evidence for the role of inflammatory mediators comes from the fact that both COX inhibitors and thromboxane-A2 receptor antagonists have been shown to restore endothelial-dependent vasorelaxation in the diabetic state.  Antioxidants have been shown to improve endothelial dependent vasodilation in animal models of diabetes.  It is clear that oxidative stress represents an important contributing factor for the pathogenesis of the impairment of endothelium dependent vasorelaxation seen in metabolic syndrome.  These vascular changes have been speculated to play a role in the pathogenesis for development of laminitis in EMS affected patients.

            

Metabolic Syndrome and Glucocorticoids

Situations of GC excess such as stress or pituitary dysfunction may stimulate the production of hormonally active adipocytes that lead to metabolic syndrome.  Interestingly the active adipocytes contain an enzyme called 11beta-hydroxysteroid dehydrogenase type-1 (11betaHSD-1).  This enzyme has the critical function of turning inactive cortisone into active cortisol which is the active glucocorticoid.  This production of cortisol occurs locally and exerts both paracrine (local) and autocrine (back to the originating cell) effects.    Therefore, these adipocytes, due to the presence of 11betaHSD-1 have the capacity to maintain and perpetuate themselves.  The overall extent to which 11betaHSD-1 generated cortisol exerts effects in the body as a whole, remains to be determined.  New strategies aimed at inhibiting omental  11betaHSD-1 production are believed to be potentially useful for the management of metabolic syndrome.  Moreover, although the effects of GC are apparent it is important to recognize that this is not a condition of abnormal adrenal function.  Even though GC are involved in the pathogenesis of disease, since adrenal function is normal, diagnostic assays designed for detection of altered circulating cortisol levels are within normal limits; subsequently, therapeutic strategies aimed at treating pituitary dysfunction will have no effect on horses with EMS unless there is concurrent pituitary dysfunction present. 

 

Clinical Management of EMS

The primary goal of control of this condition in horses is reduction in obesity.  The presence of 11betaHSD-1 in omental adipocytes contributes to the propensity to increase weight gain and presents the manager with a challenge for controlling weight gain.  Not only is restricted intake warranted, but also the implementation of adequate exercise (as can be tolerated by the potentially or clinically laminitic patient).  Exercise should only be implemented in those individuals that are non-laminitic or are well recovered from their laminitic episode.  Dietary fat should be minimized (fat enriched rations for geriatric individuals should not be fed to these patients).  Antioxidant therapy such as vitamin E (8,000-10,000 U/day) can be safely administered to adult horses.  Chromium supplementation has been reported by some authors to increase insulin sensitivity in some individuals.  In our hospital setting, it is common practice to administer 5-20 mg of chromium picolinate daily to hyperinsulinemic horses. Demonstrable reduction in serum fasting insulin levels have been observed in several patients.  Further investigation is required to more fully elucidate the effectiveness of chromium, magnesium, or vanadium supplementation in horses suffering from EMS.  The main recommendation is for reduction in body weight, particularly in those breeds where EMS is common.  Although a common practice by some individuals, feeding young growing horses high concentrate diets is not recommended due to the potential for dangerous metabolic consequences. 

 

·                     Control body condition

·                     Reduce caloric intake

·                     Maintain a regular exercise program and horse can tolerate

·                     Supplement with vitamin E (8000-10,000 U/day)

·                     Supplement with chromium picolinate (5-20 mg/day) monitor fasting serum insulin levels to aid in dosing recommendations.

·                     Antiinflammatory therapy with NSAIDs (e.g. phenylbutazone 2.2-4.4 mg/kg PO sid-bit) for management of pain associated with laminitis.

 

References: Available upon request