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Equine veterinary journal2013; 45(5); 613-618; doi: 10.1111/evj.12040

Hyperinsulinaemia increases vascular resistance and endothelin-1 expression in the equine digit.

Abstract: Insulin leads to overexpression of endothelin-1 (ET-1) in the endothelium of insulin-resistant rodents. If this is also the case in equine laminar tissue, this could explain the predisposition of insulin-resistant horses to laminitis. Objective: To investigate the effect of hyperinsulinaemia on metabolism and vascular resistance of the isolated equine digit in a model of extracorporeal perfusion. Methods: Randomised, controlled study with interventional group, with blinded evaluation of histology results. Methods: After exsanguination, equine digits (n = 11) and autologous blood were collected at an abattoir. One digit served as a hyperinsulinaemic pilot limb, 5 digits were assigned to the hyperinsulinaemic perfusion (IP) group and 5 to the control perfusion (CP) group. Digits were perfused for 10 h at a defined perfusion rate of 12 ml/min/kg. After the first hour of perfusion (equilibration period), insulin was added to the reservoir of the IP digits. Perfusion pressure, glucose consumption, lactate and lactate dehydrogenase were monitored. Vascular resistance was calculated as perfusion pressure (in millimetres of mercury) in relation to the flow rate (in millilitres per minute). After perfusion, histology samples of the dorsal hoof wall (haematoxylin & eosin or periodic acid-Schiff) were evaluated. Immunohistology with a polyclonal rabbit-derived anti-endothelin antibody was used for detection of ET-1. Results: In the IP group, the mean insulin concentration in the plasma of the perfusate was 142 ± 81 μiu/ml, while insulin concentration was <3 μiu/ml in the CP group. Mean vascular resistance was significantly higher (P<0.01) in the IP group (2.04 ± 1.13 mmHg/ml/min) than in the CP group (1.31 ± 0.55 mmHg/ml/min). Histology of the IP group samples showed significantly more vessels with an open lumen, increased width of the secondary epidermal lamellae and formation of oedema. In the lamellar vessels (veins and arteries) and nerve fibres, ET-1 expression was much more prominent in the IP group than in the CP group samples. Conclusions: Short-term hyperinsulinaemia leads to increased vascular resistance in the equine digit and increased expression of ET-1 in the laminar tissue.
© 2013 EVJ Ltd.
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Publication Date: 2013-03-12 PubMed ID: 23489109PubMed Central: PMC4018505DOI: 10.1111/evj.12040Google Scholar: Lookup
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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 investigates how increased insulin levels affect blood vessel resistance and the expression of endothelin-1 (a protein) in horse tissue. The study’s findings imply that horses with insulin resistance may be more prone to laminitis, a painful hoof condition.

Study Design and Methodology

  • The study was designed as a randomized, controlled experiment involving 11 equine digits (hooves) collected from an abattoir. It also involved autologous blood from the horses.
  • The hooves were divided into two groups: a control group and a group subjected to artificially induced hyperinsulinemia (extremely high insulin levels).
  • Each hoof was subjected to extracorporeal perfusion for ten hours, with a controlled perfusion rate. In this process, the blood in the hoof was replaced with a perfusion solution to observe the effect of different insulin levels on tissue behaviour.
  • After the first hour of perfusion, insulin was added to the reservoir of the hyperinsulinemia group’s digits. Various parameters such as perfusion pressure, glucose consumption, lactate, and lactate dehydrogenase levels were monitored.
  • Vascular resistance, a measure of the difficulty of blood-flow through the vessels, was calculated in each sample. Any changes were linked to the varying insulin levels in the two groups.
  • Post-perfusion, these tissue samples were subjected to histological and immunohistological analysis to evaluate structural changes and to detect endothelin-1 expression.

Findings

  • In the group with induced hyperinsulinemia, the insulin concentration in the plasma was noticeably higher than in the control group.
  • The study found an increase in vascular resistance in the group exposed to hyperinsulinemia – indicating difficulty in blood flow.
  • The hyperinsulinemic group also showed increased expression of endothelin-1 in the sampled lamellar tissue – a protein typically overexpressed in insulin resistance.
  • There were also notable histological changes in the hyperinsulinemic group such as more vessels with open lumen, increased width of the secondary epidermal lamellae, and formation of edema (swelling).

Conclusions

  • The research concluded that short-term hyperinsulinemia leads to increased vascular resistance and increased expression of endothelin-1 in horse hoof tissue.
  • These findings could potentially explain why horses with insulin resistance are more prone to laminitis, a debilitating hoof condition. Further research is needed to fully understand the implications of these findings and potential therapeutic strategies.

Cite This Article

APA
Gauff F, Patan-Zugaj B, Licka TF. (2013). Hyperinsulinaemia increases vascular resistance and endothelin-1 expression in the equine digit. Equine Vet J, 45(5), 613-618. https://doi.org/10.1111/evj.12040

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 45
Issue: 5
Pages: 613-618

Researcher Affiliations

Gauff, F
  • Clinic of Orthopaedics in Large Animals, Department of Horses and Small Animals, Vienna University of Veterinary Medicine, Austria. felicia.gauff@vetmeduni.ac.at
Patan-Zugaj, B
    Licka, T F

      MeSH Terms

      • Animals
      • Cadaver
      • Endothelin-1 / genetics
      • Endothelin-1 / metabolism
      • Gene Expression Regulation
      • Horses / metabolism
      • Hyperinsulinism / veterinary
      • Insulin / pharmacology
      • Perfusion

      Grant Funding

      • P 22598 / Austrian Science Fund FWF

      References

      This article includes 31 references
      1. Frank N, Geor RJ, Bailey SR, Durham AE, Johnson PJ. Equine metabolic syndrome.. J. Vet. Intern. Med. 2010;24:467–475.
        pubmed: 20384947
      2. Bailey SR, Menzies-Gow NJ, Harris PA, Habershon-Butcher JL, Crawford C, Berhane Y, Boston RC, Elliott J. Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis.. J. Am. Vet. Med. Assoc. 2007;231:1365–1373.
        pubmed: 17975996
      3. Asplin KE, Sillence MN, Pollitt CC, McGowan CM. Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies.. Vet. J. 2007;174:530–535.
        pubmed: 17719811
      4. De Laat MA, McGowan CM, Sillence MN, Pollitt CC. Equine laminitis: induced by 48 h hyperinsulinaemia in Standardbred horses.. Equine Vet. J. 2010;42:129–135.
        pubmed: 20156248
      5. De Laat MA, Sillence MN, McGowan CM, Pollitt CC. Continuous intravenous infusion of glucose induces endogenous hyperinsulinaemia and lamellar histopathology in Standardbred horses.. Vet. J. 2012;191:317–322.
        pubmed: 21873088
      6. Venugopal CS, Eades S, Holmes EP, Beadle RE. Insulin resistance in equine digital vessel rings: an in vitro model to study vascular dysfunction in equine laminitis.. Equine Vet. J. 2011;43:744–749.
        pubmed: 21496102
      7. Kim J, Montagnani M, Koh KK, Quon MJ. Reciprocal relationship between insulin resitance and endothelial dysfunction: molecular and pathophysiological mechanisms.. Circulation. 2006;113:1888–1904.
        pubmed: 16618833
      8. Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, Montagnani M. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production.. Am. J. Physiol. Heart Circ. Physiol. 2005;289:H813–H822.
        pubmed: 15792994
      9. Peroni JF, Moore JN, Noschka E, Grafton ME, Aceves-Avila M, Lewis SJ, Robertson TP. Predisposition for venoconstriction in the equine laminar dermis: implications in equine laminitis.. J. Appl. Physiol. 2006;100:759–763.
        pubmed: 16269525
      10. Eaton SA, Allen D, Eades SC, Schneider DA. Digital Starling forces and hemodynamics during early laminitis induced by an aqueous extract of black walnut (Juglans nigra) in horses.. Am. J. Vet. Res. 1995;56:1338–1344.
        pubmed: 8928952
      11. Patan B, Budras KD, Licka TF. Effects of long-term extracorporeal blood perfusion of the distal portion of isolated equine forelimbs on metabolic variables and morphology of laminar tissue.. Am. J. Vet. Res. 2009;70:669–677.
        pubmed: 19405908
      12. Patan-Zugaj B, Gauff FC, Licka TF. Effects of the addition of endotoxin during perfusion of isolated forelimbs of equine cadavers.. Am. J. Vet. Res. 2012;73:1462–1468.
        pubmed: 22924729
      13. Berhane Y, Elliott J, Bailey SR. Assessment of endothelium-dependent vasodilation in equine digital resistance vessels.. J. Vet. Pharmacol. Ther. 2006;29:387–395.
        pubmed: 16958783
      14. Henneke DR, Potter GD, Kreider JL, Yeates BF. Relationship between condition score, physical measurements and body fat percentage in mares.. Equine Vet. J. 1983;15:371–372.
        pubmed: 6641685
      15. Carter RA, McCutcheon LJ, George LA, Smith TL, Frank N, Geor RJ. Effects of diet-induced weight gain on insulin sensitivity and plasma hormone and lipid concentrations in horses.. Am. J. Vet. Res. 2009;70:1250–1258.
        pubmed: 19795940
      16. Keen JA, Hillier C, McGorum BC, Nally JE. Endothelin mediated contraction of equine laminar veins.. Equine Vet. J. 2008;40:488–492.
        pubmed: 18487099
      17. Asplin KE, Curlewis JD, McGowan CM, Pollitt CC, Sillence MN. Glucose transport in the equine hoof.. Equine Vet. J. 2011;43:196–201.
        pubmed: 21592215
      18. Pass MA, Pollitt S, Pollitt CC. Decreased glucose metabolism causes separation of hoof lamellae in vitro: a trigger for laminitis?. Equine Vet. J. Suppl. 1998;26:133–138.
        pubmed: 9932104
      19. Lv G, Shi H, Fan L, Feng Z, Wang G. Intensive insulin treatment protected the cardiac myocytes against apoptosis in severely scalded rats.. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23:714–717.
        pubmed: 22153006
      20. Wagner SM, Nogueira AC, Paul M, Heydeck D, Klug S, Christ B. The isolated normothermic hemoperfused porcine forelimb as a test system for transdermal absorption studies.. J. Artif. Organs. 2003;6:183–191.
        pubmed: 14598102
      21. Zanatta CM, Veríonese FV, Da Silva Loreto M, Sortica DA, Carpio VN, Eldeweiss MIA, Da Silva VD, Lopes TG, Gross JL, Canani LH. Endothelin-1 and endothelin A receptor immunoreactivity is increased in patients with diabetic nephropathy.. Ren. Fail. 2012;34:308–315.
        pubmed: 22250646
      22. Katz LM, Marr CM, Elliott J. Characterization and comparison of the responses of equine digital arteries and veins to endothelin-1.. Am. J. Vet. Res. 2003;64:1438–1443.
        pubmed: 14620782
      23. Bailey SR, Habershon-Butcher JL, Ransom KJ, Elliott J, Menzies-Gow NJ. Hypertension and insulin resistance in a mixed-breed population of ponies predisposed to laminitis.. Am. J. Vet. Res. 2008;69:122–129.
        pubmed: 18167097
      24. Treiber KH, Kronfeld DS, Hess TM, Byrd BM, Splan RK, Staniar WB. Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies.. J. Am. Vet. Med. Assoc. 2006;228:1538–1545.
        pubmed: 16677122
      25. Leise BS, Faleiros RR, Watts M, Johnson PJ, Black SJ, Belknap JK. Laminar inflammatory gene expression in the carbohydrate overload model of equine laminitis.. Equine Vet. J. 2011;43:54–61.
        pubmed: 21143634
      26. Bailey SR, Wheeler-Jones C, Elliott J. Uptake of 5-hydroxytryptamine by equine digital vein endothelial cells: inhibition by amines found in the equine caecum.. Equine Vet. J. 2003;35:164–169.
        pubmed: 12638793
      27. Menzies-Gow NJ, Bailey SR, Katz LM, Marr CM, Elliott J. Endotoxin-induced digital vasoconstriction in horses: associated changes in plasma concentrations of vasoconstrictor mediators.. Equine Vet. J. 2004;36:273–278.
        pubmed: 15147137
      28. Post IC, Dirkes MC, Heger M, Bezemer R, van ’t Leven J, van Gulik TM. Optimal flow and pressure management in machine perfusion systems for organ preservation.. Ann. Biomed. Eng. 2012;40:2698–2707.
        pmc: PMC3508271pubmed: 22669502
      29. Peroni JF, Harrison WE, Moore JN, Graves JE, Lewis SJ, Krunkosky TM, Robertson TP. Black walnut extract-induced laminitis in horses is associated with heterogeneous dysfunction of the laminar microvasculature.. Equine Vet. J. 2005;37:546–551.
        pubmed: 16295933
      30. De Laat MA, van Eps AW, McGowan CM, Sillence MN, Pollitt CC. Equine laminitis: comparative histopathology 48 hours after experimental induction with insulin or alimentary oligofructose in standardbred horses.. J. Comp. Pathol. 2011;145:399–409.
        pubmed: 21429503
      31. Finding EJT, Jones ID, Fuentes VL, Menzies-Gow NJ. Evaluation of a technique for measurement of flow-mediated vasodilation in healthy ponies.. Am. J. Vet. Res. 2012;73:755–761.
        pubmed: 22620687

      Citations

      This article has been cited 8 times.
      1. 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.
        doi: 10.1111/jvp.13470pubmed: 38984777google scholar: lookup
      2. Fegraeus K, Rosengren MK, Naboulsi R, Orlando L, Åbrink M, Jouni A, Velie BD, Raine A, Egner B, Mattsson CM, Lång K, Zhigulev A, Björck HM, Franco-Cereceda A, Eriksson P, Andersson G, Sahlén P, Meadows JRS, Lindgren G. An endothelial regulatory module links blood pressure regulation with elite athletic performance. PLoS Genet 2024 Jun;20(6):e1011285.
        doi: 10.1371/journal.pgen.1011285pubmed: 38885195google scholar: lookup
      3. 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.
        doi: 10.1111/jvim.15835pubmed: 32583504google scholar: lookup
      4. Unterköfler MS, McGorum BC, Milne EM, Licka TF. Establishment of a model for equine small intestinal disease: effects of extracorporeal blood perfusion of equine ileum on metabolic variables and histological morphology - an experimental ex vivo study. BMC Vet Res 2019 Nov 8;15(1):400.
        doi: 10.1186/s12917-019-2145-9pubmed: 31703590google scholar: lookup
      5. 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.
        doi: 10.1111/jvim.15423pubmed: 30724412google scholar: lookup
      6. Nostell KE, Lindåse SS, Bröjer JT. Blood pressure in Warmblood horses before and during a euglycemic-hyperinsulinemic clamp. Acta Vet Scand 2016 Oct 20;58(Suppl 1):65.
        doi: 10.1186/s13028-016-0247-ypubmed: 27766986google scholar: lookup
      7. Menzies-Gow NJ, Wray H, Bailey SR, Harris PA, Elliott J. The effect of tumour necrosis factor-α and insulin on equine digital blood vessel function in vitro. Inflamm Res 2014 Aug;63(8):637-47.
        doi: 10.1007/s00011-014-0736-2pubmed: 24764104google scholar: lookup
      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.
        doi: 10.2460/ajvr.75.4.367pubmed: 24669922google scholar: lookup
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