IN-DEPTH: ENDOCRINOLOGY IN GERIATRICS


nal involvement or systemic illness throughout the experiments.12,13 The hyperinsulinemic model of laminitis has al-


lowed us to explore different mechanisms that are possibly involved in the development of endocrino- pathic laminitis. Prior research does not support glucose deprivation29 or glucose excess30 as under- lying mechanisms. Metalloproteinases (MMP2 and MMP9 and ADAMTS4) have been consistently upregulated in SIRS or sepsis models of laminitis.31 However, this has not been the case in hyperinsulinemic laminitis where minimal MMP or ADAMTS4 activity during the developmental and acute stages of laminitis oc- curred and only MMP9 was upregulated at later stages of laminitis (48 hours), correlating with his- tological evidence of neutrophil infiltration.32


Mechanisms of Hyperinsulinemia and Laminitis


More recently insulin’s effect on signaling within cells and its effects on blood flow have provided important mechanistic clues. Insulin, when it is working via its appropriate intracellular pathways, has marked effects on stimulating vasodilation and blood flow in both small and large vessels via nitric oxide–mediated pathways.33 Insulin resistance re- sults in inappropriate intracellular pathway activa- tion leading to the opposite effects, which in the vascular endothelium leads to vasoconstriction. Ex-vivo vascular ring models from equine digital vessels showed that just 30 minutes pre-incubation in insulin (inducing insulin dysfunction) resulted in an inappropriate vasoconstriction response to the addition of insulin.34 This effect was obliterated by a blocker of the inappropriate intracellular pathway of insulin signaling.34 Further work in horse vas- culature has supported this first study finding the same results using laminar vessels.35 This was further supported by comparing the vascular re- sponses from naturally occurring endocrinopathic laminitis horses and controls using laminar arteries and veins and facial arteries.36 Vascular dysfunc- tion was evident in the vessels derived from endocri- nopathic animals but not the controls.36 Together there is now compelling evidence that hyperinsulin- emia associated with either the hyperinsulinemia model or naturally occurring insulin dysregulation in- duces abnormal insulin signaling at a cellular level, at least in the vascular endothelium. However, the vascular endothelium is only part of


the story and does not correlate well with the histo- logical lesion which provides even more important mechanistic clues.1 As early as 6 hours post expo- sure to hyperinsulinemia, marked elongation of the secondary epidermal laminae (SEL) is observed, de- veloping tapered tips and with SEL angled more acutely to the primary lamellar (PEL) axis.37 Cel- lular changes are dominated by cellular elongation and stretching then apoptosis and mitosis, all of which precede the pain and inflammation of Obel grade 2 laminitis.38 The current theory of endocri-


nopathic laminitis is that the epithelial cells that make up the laminae are affected by hyperinsulin- aemia, just like the vascular endothelial cells were shown to be affected above, resulting in abnormal intracellular signaling in insulin dysregulated horses. This results in activation and dysregula- tion of certain pathways or “downstream events” within the cells resulting in cellular damage and disruption of cytoskeletal organization, allowing these cells to stretch under mechanical forces and leading to the well-defined initial lesion of laminar and cellular stretching.1,39


PPID and Insulin Dysregulation


Although it is known that over a third of horses with PPID are insulin dysregulated, and that insulin dys- regulation causes the laminitis, it is not entirely clear how PPID induces insulin dysregulation. Due to the high prevalence of PPID (over 20%)23 and also of insulin dysregulation without PPID (EMS; over 25% in susceptible breeds such as ponies),40 and the fact that in both conditions the prevalence increases with age23,40 it is possible that both con- ditions could simply be occurring in the same ani- mal. It may be that PPID itself does not cause insulin dysregulation at all and laminitis only oc- curs when PPID occurs in an animal that already had insulin dysregulation. However, this is not supported by the observation that horses with PPID were 2.7 times more likely to have hyperinsulinemia than aged matched controls.23 Several mechanisms have been considered as to


why PPID may lead to insulin dysregulation includ- ing abnormal central or peripheral glucocorticoid activity.17 Although much of the secreted ACTH in horses with PPID may be biologically inactive or inert19 and circulating cortisol may not be elevated in horses with PPID,41 there could be local upregu- lation of corticosteroids in peripheral tissues such as adipose tissue.17 Evidence for prolonged glucocor- ticoid administration inducing insulin dysregulation exists.42 Or it could be that pituitary peptides such as CLIP interfere with insulin regulation.19 But ultimately, the relationship between PPID and the development of insulin dysregulation is not com- pletely known. Irrespective of how horses with PPID develop in-


sulin dysregulation, it is increasingly apparent that the combination of PPID and insulin dysregulation leads to a poorer prognosis than either PPID horses without insulin dysregulation41 or than insulin- dysregulated horses without PPIDa.


Conclusions and Clinical Implications


Laminitis is a clinical syndrome with a cause, and endocrinopathic laminitis accounts for over 90% of laminitis cases seen in the field for lameness. There- fore, for laminitis that presents as lameness, clinical evaluation can often rapidly eliminate SIRS and sepsis-associated conditions and supporting limb laminitis as potential causes. If these are ruled


AAEP PROCEEDINGS  Vol. 64  2018 185


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