South African Equine Veterinary Association Congress 2015 Protea Hotel Stellenbosch
the retina or kidney. Further, biomarkers of glucotoxicity (advanced glycation end products and
reactive oxygen species) are not found in the early stages of the hyperinsulinemic-euglycemic
clamp model of laminitis induction. Consequently, glucose toxicity does not appear to be a trigger
for development of laminitis. Subsequent research focused on activation of matrix
metalloproteases (MMPs) that would disrupt the basement membrane that is the glue between the
sensitive and insensitive lamina. However, upregulation and activation of MMPs is not an early
finding in hyperinsulinemic experimental models. Further, early histological changes in this
model include stretching and retraction of secondary lamina from the basement membrane, rather
than disruption of the basement membrane. Recently, more detailed histological examination of
laminar tissue collected from horses undergoing the hyperinsulinemic model of laminitis
induction have shown both apoptosis (programmed cell death) and mitogenesis (increased
numbers of dividing cells) in the secondary dermal lamina, focused in the axial region (closer to
the third phalanx) of the laminar bed. Again, the connection(s) between these histological changes
and development of laminitis remain to be elucidated.
Insulin has a broader range of actions than simply enhancing tissue glucose uptake. Specifically,
insulin can act as a pro-inflammatory agent stimulating inflammatory mediator production (e.g.,
tumour necrosis factor-α, interleukin-6, and others) and hemodynamic alterations
(vasoconstriction and hypertension). Further, endothelial cells are particularly susceptible to the
effects of excess insulin and glucose. Specifically, there is a reduction in endothelial-derived
nitric oxide (NO) activity and increased expression of endothelin-1 (ET-1). The combination of
reduced NO and enhanced ET-1 production leads to an increased state of vasospasticity because
NO and ET-1 represent the two most potent endothelium-derived vasorelaxing and
vasocontracting factors, respectively. The role of these hemodynamic changes on the development
of laminitis in obese horses is currently unknown but it is becoming increasingly evident that the
traditional “vascular hypothesis” and more recently described “metabolic hypothesis” for
development of laminitis are not mutually exclusive.
Next, both endogenous and exogenous corticosteroids can alter insulin action leading to changes
in uptake and release of glucose and fatty acids by hepatic, adipose, and muscle tissue. Syndromes
of cortisol excess, such as PPID, can also lead to decreased tissue uptake of glucose and IR,
sometimes manifested by hyperglycemia and hyperinsulinemia. With EMS, serum cortisol
concentration is not elevated (and is often nearer the lower end of the reference range) and results
of overnight dexamethasone suppression tests are normal. However, cortisol activity at the tissue
level is largely regulated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-βHSD1). This enzyme has both oxo-reductase and dehydrogenase activities. Dehydrogenase
activity of this enzyme converts active cortisol to inactive cortisone. In contrast, oxo-reductase
activity of this enzyme results in greater conversion of inactive cortisone to active cortisol in the
tissues, thereby magnifying the effects of circulating glucocorticoids on target tissues. Because the
alteration in cortisol metabolism occurs at the tissue level, rather than through the hypothalamicpituitary-adrenal axis, the terms “Cushing‟s disease of the omentum” and “peripheral Cushing‟s
syndrome” were early descriptors used for the metabolic syndrome.
A number of further metabolic alterations can accompany both human and equine metabolic
syndrome. However, obesity is the primary problem that sets off the cascade of metabolic
abnormalities. In humans, excess fat can either be deposi ted centrally (android or apple-shaped
individuals) or around the hips (gynoid or pear-shaped individuals). The former are typically
insulin resistant and may have hyperinsulinemia while the latter typically are not insulin resistant.
One mechanism that appears to contribute to IR in android individuals is excess fat storage in
liver and skeletal muscle, perhaps because adipocytes in other areas of the body are less effective
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