Equine Metabolic Syndrome
In the past decade a condition has been recognized
with increasing frequency called equine metabolic syndrome (
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
Horses affected with
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
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
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
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
· 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.
therapy with NSAIDs (e.g. phenylbutazone 2.2-4.4 mg/kg
References: Available upon request