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PloS one2020; 15(9); e0239261; doi: 10.1371/journal.pone.0239261

Effects of an anti-IGF-1 receptor monoclonal antibody on laminitis induced by prolonged hyperinsulinaemia in Standardbred horses.

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.
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Publication Date: 2020-09-29 PubMed ID: 32991593PubMed Central: PMC7524003DOI: 10.1371/journal.pone.0239261Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explores the effects of an anti-IGF-1 receptor monoclonal antibody on a type of foot disease in horses called laminitis induced by extended periods of high insulin levels. The results show that this antibody could potentially contribute to preventing or treating the disease.

Overview of Research

  • This research is aimed at understanding the effects of an anti-IGF-1 receptor monoclonal antibody in a horse foot disease called laminitis which is caused by prolonged high insulin levels (hyperinsulinaemia).
  • There is currently no registered treatment for this type of laminitis and the underlying mechanism of how high insulin levels cause this is not well understood.
  • One hypothesis is the high levels of insulin activate IGF-1 receptors in the foot tissue which then leads to uncontrolled cell growth and regulation issues.

Methodology and Experimental Setup

  • An equinized version or horse-compatible form of the human anti-IGF-1R monoclonal antibody was developed to test the above hypothesis.
  • The researchers experimented on healthy Standardbred horses by infusing them with saline as a negative control, a combination of insulin and glucose to maintain balanced blood sugar levels as a positive control, or insulin and glucose after a low dose of the newly developed antibody.
  • The antibody was designed to treat one foot only and was administered via backward infusion in one of the forelimbs.

Findings of the Experiment

  • All horses that were treated with insulin developed laminitis within 30 hours as confirmed through clinical examination, foot radiographs and microscopic analysis.
  • However, horses that were treated with the antibody showed less sinking of the distal phalanx and milder histological changes with visibly less elongation at the tips of the secondary epidermal lamellae.
  • These changes were significant when compared to the positive control group, suggesting that the antibody had an effect on the development of laminitis.

Conclusion and Future Research

  • The results from the experiment confirm that IGF-1 receptors may indeed have a role in causing laminitis in horses.
  • The experiment also suggests that the anti-IGF-1 receptor monoclonal antibody can potentially prevent or act as a treatment for the disease.
  • However, since some effects of insulin were not mitigated by the antibody, further research and experimentation are necessary.

Cite This Article

APA
Rahnama S, Vathsangam N, Spence R, Medina-Torres CE, Pollitt CC, de Laat MA, Bailey SR, Sillence MN. (2020). Effects of an anti-IGF-1 receptor monoclonal antibody on laminitis induced by prolonged hyperinsulinaemia in Standardbred horses. PLoS One, 15(9), e0239261. https://doi.org/10.1371/journal.pone.0239261

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 15
Issue: 9
Pages: e0239261
PII: e0239261

Researcher Affiliations

Rahnama, Samira
  • Biology and Environmental Sciences School, Queensland University of Technology, Brisbane, Queensland, Australia.
Vathsangam, Niveditha
  • Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
Spence, Robert
  • Biology and Environmental Sciences School, Queensland University of Technology, Brisbane, Queensland, Australia.
Medina-Torres, Carlos E
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Pollitt, Christopher C
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
de Laat, Melody A
  • Biology and Environmental Sciences School, Queensland University of Technology, Brisbane, Queensland, Australia.
Bailey, Simon R
  • Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
Sillence, Martin N
  • Biology and Environmental Sciences School, Queensland University of Technology, Brisbane, Queensland, Australia.

MeSH Terms

  • Animals
  • Antibodies, Anti-Idiotypic / immunology
  • Antibodies, Anti-Idiotypic / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Cell Proliferation / drug effects
  • Epidermis / drug effects
  • Glucose / metabolism
  • Horse Diseases / drug therapy
  • Horse Diseases / immunology
  • Horses
  • Hyperinsulinism / drug therapy
  • Hyperinsulinism / immunology
  • Hyperinsulinism / pathology
  • Hyperinsulinism / veterinary
  • Insulin / immunology
  • Insulin / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / immunology

Conflict of Interest Statement

The authors have read the journal's policy and the authors of this paper declare the following competing interests: This study received funding from the commercial companies Nexvet Biopharma and Zoetis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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Citations

This article has been cited 3 times.
  1. Loos C, Castelein A, Vanzant E, Adam E, McLeod KR. Nutraceutical Supplement Mitigates Insulin Resistance in Horses with a History of Insulin Dysregulation During a Challenge with a High-Starch Diet. Animals (Basel) 2024 Nov 25;14(23).
    doi: 10.3390/ani14233385pubmed: 39682351google scholar: lookup
  2. Skelton G, Acutt E, Stefanovski D, van Eps A. Evaluation of digital radiographic measurements for the diagnosis of acute laminitis. Equine Vet J 2025 Jul;57(4):931-942.
    doi: 10.1111/evj.14436pubmed: 39568299google scholar: lookup
  3. Mendoza FJ, Toribio RE, Perez-Ecija A. Metabolic and Endocrine Insights in Donkeys. Animals (Basel) 2024 Feb 10;14(4).
    doi: 10.3390/ani14040590pubmed: 38396558google scholar: lookup
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