Characterization of insulin and IGF-1 receptor binding in equine liver and lamellar tissue: implications for endocrinopathic laminitis.
Authors: S. Nanayakkara, S. Rahnama, P. Harris, S. T. Anderson, M. D. de Laat, S. Bailey, M. Sillence
Journal: Domestic animal endocrinology
Summary
# Editorial Summary: Insulin Action Mechanisms in Endocrinopathic Laminitis Whilst hyperinsulinemia's role in triggering equine laminitis is clinically well recognised, the precise biochemical mechanism by which excessive insulin damages the lamellae remains unclear. Nanayakkara and colleagues employed radioligand-binding analysis on tissue samples from horses' livers and lamellar tissue to characterise receptor populations and determine their binding affinities for insulin and IGF-1. The research revealed abundant IGF-1 receptors in lamellar tissue (KD 0.16 nM) but negligible insulin receptor presence (estimated Bmax 14 fmol/mg protein), which initially suggested insulin-induced laminitis might operate through cross-activation of IGF-1 receptors—however, insulin demonstrated extraordinarily poor affinity for equine IGF-1 receptors (Ki 934 nM), more than 5,800-fold weaker than IGF-1's binding, rendering this mechanism physiologically implausible even at pathological insulin concentrations. These findings necessitate investigation of alternative pathways through which hyperinsulinemia exerts its damaging effects on lamellar tissue, potentially involving indirect mechanisms such as altered glucose metabolism, vascular dysfunction, or inflammatory cascades rather than direct receptor-mediated signalling. For practitioners managing insulin dysregulation, this work underscores that hyperinsulaemic laminitis likely involves complex systemic effects beyond simple receptor activation, reinforcing the importance of aggressive insulin control through diet, exercise and pharmaceutical intervention rather than assuming single-pathway pathology.
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Practical Takeaways
- •High insulin levels cause laminitis through a mechanism that does NOT involve direct binding to IGF-1 receptors in the lamellae—the cause remains to be identified and may involve systemic metabolic effects rather than local receptor activation
- •Managing endocrinopathic laminitis through insulin control remains critical, but understanding the true mechanism of insulin injury may lead to more targeted therapeutic approaches beyond glucose/insulin regulation alone
- •Current research does not support IGF-1 receptor antagonism as a therapeutic strategy for insulin-associated laminitis
Key Findings
- •Lamellar tissue contains abundant IGF-1 receptors (KD 0.16 nM, Bmax 243 fmol/mg protein) but sparse insulin receptors (estimated Bmax 14 fmol/mg protein)
- •Insulin has >5,800-fold lower affinity for equine lamellar IGF-1 receptors (Ki 934 nM) compared to IGF-1, making insulin binding at physiological concentrations unlikely
- •Insulin receptors were detected in liver but barely detectable in lamellae, contradicting the hypothesis that insulin causes laminitis via IGF-1 receptor binding
- •No evidence of insulin/IGF-1 hybrid receptors in liver or lamellar tissue, requiring alternative mechanisms to explain hyperinsulinemia-induced laminitis