Abstract
Currently, there are no registered veterinary drugs for the treatment of endocrinopathic equine laminitis, and although this form of the disease is known to be caused by prolonged hyperinsulinaemia, the mechanism of insulin toxicity is unclear. One possibility is that high concentrations of insulin activate IGF-1 receptors (IGF-1R) in lamellar tissue, leading to uncontrolled cell proliferation and epidermal lamellar dysregulation. An equinized version of a human anti-IGF-1R therapeutic monoclonal antibody (mAb11) was generated to test this theory, using a modification of the prolonged euglycaemic-hyperinsulinaemic clamp technique. Healthy Standardbred horses were infused for 48 h with 0.9% saline (negative-control, n = 6), a combination of insulin (4.5 mIU/kgBW/min) and a variable infusion of 50% glucose to maintain euglycaemia (positive-control, n = 6), or insulin and glucose, preceded by a low dose of mAb11 (20 mg), designed to treat one foot only and delivered by retrograde infusion into one forelimb (mAb-treated, n = 7). Maximum insulin concentrations were 502 ± 54.4 and 435 ± 30.4 μIU/mL in the positive-control and mAb11-treated groups, respectively (P = 0.33). While the control group remained healthy, all the insulin-treated horses developed laminitis within 30 h, as judged by clinical examination, foot radiographs and histological analysis. Some effects of insulin were not attenuated by the antibody, however, relative to the positive-control group, horses treated with mAb11 showed less sinking of the distal phalanx (P < 0.05) and milder histological changes, with markedly less elongation at the tips of the secondary epidermal lamellae (P < 0.05). These differences were apparent in both front feet and were statistically significant when the values for both feet were combined. The results confirm that IGF-1R may have a role in insulin-induced laminitis and suggest that mAb11 warrants further research as a potential agent to prevent or treat the disease.
Highlights
IntroductionThe development of effective treatments for this form of laminitis has been hampered by an incomplete understanding of the pathophysiology of the disease
Because there is no convenient cure for endocrinopathic equine laminitis, a common disease of the horse’s foot, the condition has been known to claim the lives of up to 33% of affected animals within 12 months of diagnosis [1], and to recur in 34% of individuals within two years [2].The development of effective treatments for this form of laminitis has been hampered by an incomplete understanding of the pathophysiology of the disease
It has been clearly established that insulin dysregulation is a primary underlying factor, as hyperinsulinaemia is commonly observed in naturally-occurring cases [3], and in a dietary induction model, where the risk and speed of onset of the disease were clearly associated with postprandial insulin concentrations [4]
Summary
The development of effective treatments for this form of laminitis has been hampered by an incomplete understanding of the pathophysiology of the disease. It has been clearly established that insulin dysregulation is a primary underlying factor, as hyperinsulinaemia is commonly observed in naturally-occurring cases [3], and in a dietary induction model, where the risk and speed of onset of the disease were clearly associated with postprandial insulin concentrations [4]. The hypothesis is supported by the observation that IGF-1R gene expression is downregulated during the insulin-induction model in vivo, in the absence of elevated plasma IGF-1 concentrations [9]. Insulin can stimulate cell proliferation in isolated lamellar cells in vitro, and that this effect can be blocked using a selective anti-human IGF-1R monoclonal antibody (mAb) [10]
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