Distribution of insulin receptor and insulin-like growth factor-1 receptor in the digital laminae of mixed-breed ponies: an immunohistochemical study.
Abstract: Hyperinsulinaemia has been implicated in the pathogenesis of laminitis; however, laminar cell types responding to insulin remain poorly characterised. Objective: To identify laminar cell types expressing insulin receptor (IRc) and/or insulin-like growth factor-1 receptor (IGF-1R); and to evaluate the effect of dietary nonstructural carbohydrate (NSC) on their expression. Methods: Mixed-breed ponies (n = 22) received a conditioning hay chop diet (NSC ∼6%); following acclimation, ponies were stratified into lean (n = 11, body condition score [BCS]≤4) or obese (n = 11, BCS ≥7) groups and each group further stratified to remain on the low NSC diet (n = 5 each for obese and lean) or receive a high NSC diet (total diet ∼42% NSC; n = 6 each for obese and lean) for 7 days. Laminar samples were collected at the end of the feeding protocol and stained immunohistochemically for IRc and IGF-1R. The number of IRc(+) cells was quantified; distribution of IGF-1R was qualitatively described. Laminar IRc content was assessed via immunoblotting. Results: The number of IRc(+) cells was greater in the laminae of high NSC ponies than low NSC ponies (P = 0.001); there was a positive correlation between the change in serum insulin concentration and number of IRc(+) cells (r(2) = 0.74; P<0.0001). No epithelial IRc(+) cells were observed; IRc(+) cells were absent from the deep dermis. Analysis of serial sections identified IRc(+) cells as endothelial cells. The distribution of IGF-1R was more extensive than that of IRc, with signal in vascular elements, epithelial cells and fibroblasts. Conclusions: Increased dietary NSC results in increased laminar endothelial IRc expression. Laminar keratinocytes do not express IRc, suggesting that insulin signalling in laminar epithelial cells must be mediated through other receptors (such as IGF-1R). Conclusions: Manipulation of signalling downstream of IRc and IGF-1R may aid in treatment and prevention of laminitis associated with hyperinsulinaemia.
© 2012 EVJ Ltd.
Publication Date: 2012-08-24 PubMed ID: 22924550DOI: 10.1111/j.2042-3306.2012.00631.xGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research indicates that a rise in dietary nonstructural carbohydrates (NSCs) increases the amount of insulin receptors (IRc) in laminar endothelial cells of ponies. These receptors, along with insulin-like growth factor-1 receptors (IGF-1R), could potentially be manipulated to treat or prevent laminitis, an inflammation in hooves associated with high levels of insulin.
Study Design and Methods
- Research was conducted with 22 mixed-breed ponies. These ponies were initially fed a diet composed of approximately 6% nonstructural carbohydrates (NSCs), often found in foods like grains and certain vegetables.
- Later, these ponies were divided into two groups based on their body condition score – lean (score ≤ 4) and obese (score ≥ 7). Each group was further bifurcated, with half continuing with the low NSC diet and the other half being switched to a high NSC diet (total diet ~42% NSC).
- This dietary routine was continued for 7 days. After this period, laminae samples from the ponies’ hooves were collected.
- The samples were stained to highlight the insulin receptor (IRc) and insulin-like growth factor-1 receptor (IGF-1R). IRc-positive cells were quantified and the distribution of IGF-1R was recorded.
Key Findings
- Ponies on a high NSC diet had a greater number of IRc-positive cells in their laminae as compared to those on a low NSC diet. This rise in IRc was also positively correlated with an increase in serum insulin levels.
- No epithelial IRc-positive cells were recorded, suggesting that insulin signalling in laminar epithelial cells is regulated by other receptors, possibly IGF-1R.
- IGF-1Rs were found to be more distributed than IRc, present in vascular elements, epithelial cells, and fibroblasts.
- IRc-positive cells were identified as endothelial cells.
Implications
- The increase in IRc expression due to increased NSC in the diet suggests a potential link between diet and laminitis, a painful condition affecting the hooves of horses.
- The findings could pave the way towards new treatments for laminitis. Modifying the signalling pathways downstream of insulin and IGF-1R may offer a method of preventing or managing laminitis, which is believed to be associated with hyperinsulinaemia.
Cite This Article
APA
Burns TA, Watts MR, Weber PS, McCutcheon LJ, Geor RJ, Belknap JK.
(2012).
Distribution of insulin receptor and insulin-like growth factor-1 receptor in the digital laminae of mixed-breed ponies: an immunohistochemical study.
Equine Vet J, 45(3), 326-332.
https://doi.org/10.1111/j.2042-3306.2012.00631.x Publication
Researcher Affiliations
- Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, USA.
MeSH Terms
- Animals
- Dietary Carbohydrates / adverse effects
- Foot Diseases / chemically induced
- Foot Diseases / metabolism
- Foot Diseases / veterinary
- Gene Expression Regulation
- Horse Diseases / chemically induced
- Horse Diseases / metabolism
- Horses / metabolism
- Immunohistochemistry / veterinary
- Inflammation / chemically induced
- Inflammation / metabolism
- Inflammation / veterinary
- Insulin / metabolism
- Receptor, IGF Type 1 / genetics
- Receptor, IGF Type 1 / metabolism
- Receptor, Insulin / genetics
- Receptor, Insulin / metabolism
- von Willebrand Factor / genetics
- von Willebrand Factor / metabolism
Citations
This article has been cited 13 times.- Stefaniuk-Szmukier M, Piórkowska K, Ropka-Molik K. Equine Metabolic Syndrome: A Complex Disease Influenced by Multifactorial Genetic Factors. Genes (Basel) 2023 Jul 27;14(8).
- Rahnama S, Vathsangam N, Spence R, Medina-Torres CE, Pollitt CC, de Laat MA, Bailey SR, Sillence MN. Effects of an anti-IGF-1 receptor monoclonal antibody on laminitis induced by prolonged hyperinsulinaemia in Standardbred horses. PLoS One 2020;15(9):e0239261.
- Stokes SM, Burns TA, Watts MR, Bertin FR, Stefanovski D, Medina-Torres CE, Belknap JK, van Eps AW. Effect of digital hypothermia on lamellar inflammatory signaling in the euglycemic hyperinsulinemic clamp laminitis model. J Vet Intern Med 2020 Jul;34(4):1606-1613.
- de Laat MA, Spence RJ, Sillence MN, Pollitt CC. An investigation of the equine epidermal growth factor system during hyperinsulinemic laminitis. PLoS One 2019;14(12):e0225843.
- Durham AE, Frank N, McGowan CM, Menzies-Gow NJ, Roelfsema E, Vervuert I, Feige K, Fey K. ECEIM consensus statement on equine metabolic syndrome. J Vet Intern Med 2019 Mar;33(2):335-349.
- Baskerville CL, Chockalingham S, Harris PA, Bailey SR. The effect of insulin on equine lamellar basal epithelial cells mediated by the insulin-like growth factor-1 receptor. PeerJ 2018;6:e5945.
- Burns TA, Watts MR, Weber PS, McCutcheon LJ, Geor RJ, Belknap JK. Effect of dietary nonstructural carbohydrate content on activation of 5'-adenosine monophosphate-activated protein kinase in liver, skeletal muscle, and digital laminae of lean and obese ponies. J Vet Intern Med 2014 Jul-Aug;28(4):1280-8.
- Gauff FC, Patan-Zugaj B, Licka TF. Effect of short-term hyperinsulinemia on the localization and expression of endothelin receptors A and B in lamellar tissue of the forelimbs of horses. Am J Vet Res 2014 Apr;75(4):367-74.
- Thane K, Voth R, Klee R, Warnken T, Chukwu V, Frank N. Effects of the Sodium-Glucose Cotransporter-2 Inhibitor Velagliflozin on Insulin Concentrations in Horses With Insulin Dysregulation. J Vet Intern Med 2025 Nov-Dec;39(6):e70256.
- Zamith Cunha R, Gobbo F, Morini M, Zannoni A, Mainardi C, D'arpe L, Gramenzi A, Chiocchetti R. Distribution of endocannabinoid system receptors in the equine hoof: dysregulation as a potential therapeutic target for laminitis. Histochem Cell Biol 2025 Jul 1;163(1):71.
- 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).
- Menzies-Gow NJ, Knowles EJ. Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses. J Vet Pharmacol Ther 2025 Jan;48 Suppl 1(Suppl 1):31-40.
- Mendoza FJ, Toribio RE, Perez-Ecija A. Metabolic and Endocrine Insights in Donkeys. Animals (Basel) 2024 Feb 10;14(4).
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