Equine metabolic syndrome management: Can they ever eat grass again? (Proceedings) - Veterinary Healthcare


Equine metabolic syndrome management: Can they ever eat grass again? (Proceedings)


Management of Equine Metabolic Syndrome (EMS), the most accepted term for a syndrome of middle-aged obesity accompanied insulin resistance (IR) and insidious-onset laminitis, can be challenging as it primarily involves client education and acceptance to comply with dietary recommendations to effect substantial weight loss. In addition, an understanding of the differences in nonstructural carbohydrate content of various forages is important for appropriate dietary recommendations to be made. Next, implementation of an exercise program for both at risk and affected horses (those with laminitis) is strongly recommended for overweight ponies and horses but may difficult to implement in equids suffering from laminitis. Although medications (thyroid hormone and metformin) and dietary supplements (magnesium, chromium, vanadium, cinnamon, etc.) have been advocated to both assist with laminitis recovery and enhance weight loss, data supporting use of these agents is limited.

Endocrinopathic laminitis

Unfortunately for horses, syndromes of IR and cortisol excess (with both EMS [at the tissue level] and pituitary pars intermedia dysfunction [systemic cortisol excess]) appear to be accompanied by alterations in the integrity of the basement membrane between the epidermis and dermis of the laminar bed. Over time, weakening and degradation of the basement membrane can lead to separation of the epidermal-dermal junction and development of laminitis. The most recently advanced term for this type of laminitis is endocrinopathic laminitis. The mechanisms behind development of laminitis appear to be complex and remain incompletely understood. Nevertheless, research over the past decade has provided new insights into some of these mechanisms and may lay the groundwork for novel approaches to treatment of this devastating problem in horses.

Anatomy and physiology of the equine foot: The equine hoof is a complex epidermal-dermal structure that has evolved to support the large body mass of the horse. Although not typically thought of as skin, the hoof is actually comprised of the same basic epidermal-dermal layers as skin. However, the area of epidermal-dermal attachment has changed from a nearly straight junction to an undulating or interdigitating junction of primary and secondary lamellae. This "laminar bed" markedly increases the surface area for attachment of the epidermis (hoof capsule) to the underlying dermis, thereby, increasing the strength of attachment and capacity to support weight. The primary lamellae (600-800 within each hoof) are long finger-like projections and interdigitation of the epidermal lamellae and the dermal lamellae holds the hoof capsule onto the underlying dermis. However, the real strength of attachment is provided by the secondary lamellae that consist of numerous short projections off each primary lamella. Secondary lamellae can be thought of as velcro-like projections that provide incredible strength of attachment to the primary lamellae. At the junction of the epidermis and dermis lies the basement membrane. The basement membrane consists of a lamina lucida, a lamina densa, and extracellular matrix. Within these layers are several proteins including laminin, type IV collagen, type VII collagen, integrins, anchoring filaments, and others. In addition to forming the supporting extracellular matrix of the basement membrane, these proteins, along with others, also anchor or attach the secondary epidermal lamellae to the basal cells of the secondary dermal lamellae.

Mechanisms involved in basement membrane damage in laminitis: Epidermal tissues have somewhat different metabolic requirements and machinery than many other organs. Specifically, the epidermis has an absolute requirement for glucose as an energy substrate. Pollitt and coworkers have nicely demonstrated this glucose requirement using an in vitro hoof explant model system. When cubes of hoof material were incubated in various media, integrity of the basement membrane was lost after 48 hours of incubation in media without glucose. In contrast, integrity of the basement membrane was maintained when glucose was present in the media. Another piece of evidence, albeit indirect, is the efflux of lactate from epidermal and hoof tissue. This has been demonstrated by the finding of higher lactate concentrations in digital venous plasma than jugular venous plasma.

With an acute insult to the laminar tissue, as in spontaneous diseases or with the carbohydrate overload model for induction of laminitis, another mechanism for damage to the laminar bed is induction of matrix metalloprotease (MMP) activity. Specifically, increased amounts of the active forms of the basement membrane degrading enzymes, Eq-MMP-2 and Eq-MMP-9, have been found in laminar tissues affected by laminitis 48 hours after carbohydrate overload. Of interest, the damage to the basement membrane caused by glucose deprivation and activation of MMPs differs. With glucose deprivation, the anchoring filaments detach from the basal cells of the secondary dermal lamellae. In contrast, with activation of MMPs, the anchoring filaments and other proteins of the extracellular matrix are destroyed.

Role of cortisol in development of laminitis: Although development of laminitis with use of exogenous glucocorticoids is clinically recognized in horses, the mechanism(s) for this adverse effect of glucocorticoids has not been well established. One likely explanation is alteration in glucose uptake by tissues due to decreased tissue sensitivity to insulin under the influence of glucocorticoids. If glucocorticoid action leads to decreased glucose uptake and utilization, and glucose is absolutely required for maintenance of the integrity of the lamellar basement membrane, then glucocorticoids could lead to slow, insidious degradation of the basement membrane and eventual separation of the lamina.

Regulation of cortisol activity at the tissue level is largely mediated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-β -HSD1). In the horse's foot elevated 11-β -HSD1 oxo-reductase activity may enhance the action of cortisol on the metabolism of extracellular matrix of lamellar connective tissue and the regular turnover of anchoring filaments connecting basal cells to the lamellar basement membrane. In short, local cortisol activity may downregulate the natural turnover of the anchoring filaments in the basement membrane. In contrast to more acute insults such as grain overload in which activation of MMPs leads to rapid degradation of the basement membrane, the process with the cortisol excess is more insidious in onset. As a consequence, endocrinopathic laminitis is often subclinical and chronic before overt lameness becomes apparent.

Recently, investigators at the University of Missouri demonstrated increased 11-β -HSD1 oxo-reductase activity in both skin and laminar tissue collected from horses with both acute (carbohydrate overload model) and naturally occurring chronic laminitis. This novel finding is an attractive explanation for the long recognized syndromes of obesity-associated laminitis in horses as well as laminitis associated with pituitary pars intermedia dysfunction. However, it is also important to recognize that the pathogenesis of laminitis in both of these syndromes of endogenous glucocorticoid excess remains incompletely understood.


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