Ex vivo effects of insulin on the structural integrity of equine digital lamellae

Sandow, Cole B.; Fugler, Lee Ann; Leise, Britta S.; Riggs, Laura; Monroe, W. Todd; Totaro, Nicholas P.; Belknap, James K.; Eades, Susan C.

doi:10.1111/evj.12964

Cited by 9 publications

(12 citation statements)

References 33 publications

(43 reference statements)

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“…Following the discovery that hyperinsulinaemia can cause laminitis in the absence of insulin resistance in the EHC model , there has been growing recognition of the role of hyperinsulinaemia in naturally‐occurring cases . This, together with evidence from in vitro studies , supports the presence of a direct effect of excess insulin on the lamellae in this form of laminitis. One such key effect of insulin in experimental models appears to be activation of lamellar epithelial IGF‐1R triggering lamellar epithelial cell proliferation .…”

Section: Discussionmentioning

confidence: 99%

Continuous digital hypothermia prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Stokes

Belknap

Engiles

et al. 2019

Equine Veterinary Journal

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Summary Background Continuous digital hypothermia can prevent the development and progression of laminitis associated with sepsis but its effects on laminitis due to hyperinsulinaemia are unknown. Objectives To determine the effects of continuous digital hypothermia on laminitis development in the euglycaemic hyperinsulinaemic clamp model. Study design Randomised, controlled (within subject), blinded, experiment. Methods Eight clinically normal Standardbred horses underwent laminitis induction using the euglycaemic hyperinsulinaemic clamp model (EHC). At initiation of the EHC, one forelimb was continuously cooled (ICE), with the other maintained at ambient temperature (AMB). Dorsal lamellar sections (proximal, middle, distal) were harvested 48 h after initiation of the EHC and were analysed using histological scoring (0–3) and histomorphometry. Cellular proliferation was quantified by counting epidermal cell nuclei staining positive with an immunohistochemical proliferation marker (TPX2). Results Severe elongation and disruption of SEL with dermo‐epidermal separation (score of 3) was observed in all AMB feet at one or more section locations, but was not observed in any ICE sections. Overall 92% of the AMB sections received the most severe histological score (grade 3) and 8% were grade 2, whereas ICE sections were classified as either grade 1 (50%) or grade 2 (50%). Relative to AMB feet, ICE sections were 98% less likely to exhibit grades 2 or 3 (OR: 0.02, 95% CI 0.001, 0.365; P<0.01). Histomorphometry measurements of total and nonkeratinised primary epidermal lamellar length were significantly increased (P<0.01) in AMB limbs compared with ICE. TPX2 positive cell counts were significantly increased (P<0.01) in AMB limbs compared with ICE. Main limitations Continuous digital hypothermia was initiated before recognition of laminitis and therefore the clinical applicability requires further investigation. Conclusions Continuous digital hypothermia reduced the severity of laminitis in the EHC model and prevented histological lesions compatible with lamellar structural failure.

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Section: Discussionmentioning

confidence: 99%

Continuous digital hypothermia prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Stokes

Belknap

Engiles

et al. 2019

Equine Veterinary Journal

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“…Although it remains unclear if the relative increase in urea clearance observed in EHC horses is biologically relevant, the results of this study demonstrate that hyperinsulinaemia can cause laminitis in the absence of hypoperfusion. The hypothesis that hyperinsulinaemia causes laminitis irrespective of a vascular effect is supported by a prior in vitro study where excess insulin had an effect on lamellar explants, weakening the dermo‐epidermal attachment …”

Section: Discussionmentioning

confidence: 93%

“…Hyperinsulinaemia is now recognised as a key element of the pathophysiology of endocrinopathic laminitis, but exactly how it contributes to lesion development remains unclear . Lamellar epithelial cell stretch, disturbances of adhesion and proliferation occur in laminitis caused by hyperinsulinaemia and it has been proposed that insulin may trigger these changes by directly or indirectly activating insulin‐like growth factor‐1 receptor (IGF‐1R) on lamellar epithelial cells . However, results of a recent study question whether insulin readily binds to lamellar IGF‐1R even in an extreme hyperinsulinaemic state …”

Section: Introductionmentioning

confidence: 99%

Lamellar energy metabolism and perfusion in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Stokes

Bertin

Stefanovski

et al. 2020

Equine Veterinary Journal

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Background Hyperinsulinaemia is associated with the development of endocrinopathic laminitis; however, the mechanisms remain unclear. Objectives Evaluate the effects of hyperinsulinaemia on lamellar energy metabolism and perfusion during laminitis development. Study design In vivo experiment. Methods Eight Standardbred horses were instrumented with a microdialysis probe in the lamellae of a forelimb. A 24 hours baseline period (BASELINE) was followed by 48 hours of a continuous euglycaemic hyperinsulinaemic clamp (EHC) from 24 to 72 hours (CLAMP). Microdialysate was collected every 6 hours and analysed for glucose, lactate and pyruvate concentrations and lactate‐to‐pyruvate ratio (L:P). Microdialysis urea clearance was used to estimate lamellar tissue perfusion. Archived microdialysis samples from six identically instrumented Standardbred horses served as controls (CON). Variables were compared over time and between EHC and CON horses using a mixed‐effects linear regression model. Results Glucose concentration decreased during the CLAMP period in CON and EHC horses (P < .001), but there was no difference between CON and EHC (P > .9). Lactate concentration increased during the CLAMP period in CON and EHC horses (P < .001), however, the rate of increase was significantly higher in EHC horses relative to CON (P = .014). There was a relative increase in pyruvate concentration in EHC horses compared with CON during the CLAMP period (P = .03). L:P increased significantly in CON horses during the CLAMP period (P < .001) but not in EHC (P = .1). Urea clearance did not change in CON (P = .9) or EHC (P = .05) during the CLAMP, but did increase in EHC relative to CON (P = .02). Main limitations The effects of microdialysis probe implantation on perfusion and metabolism remain unclear. The EHC model may not mimic natural endocrinopathic laminitis. Conclusions Laminitis developed without evidence of lamellar hypoperfusion or energy stress. Therapies to improve perfusion are unlikely to affect the initial development of endocrinopathic laminitis.

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“…This ex vivo study by Cole Sandow and colleagues in the USA aimed to characterise the effects of insulin on the structural integrity of the hoof lamellae .…”

Section: Insulin and Laminitismentioning

confidence: 99%

Highlights of recent clinically relevant papers

Wright¹

2018

Equine Veterinary Education

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Ex vivo effects of insulin on the structural integrity of equine digital lamellae

Abstract: Insulin weakens the structural integrity of equine lamellar explants and an ex vivo model for evaluation of hyperinsulinaemia-induced lamellar failure was established. The summary is available in Spanish - see Supporting Information.

Cited by 9 publications

References 33 publications

Continuous digital hypothermia prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Continuous digital hypothermia prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Lamellar energy metabolism and perfusion in the euglycaemic hyperinsulinaemic clamp model of equine laminitis

Highlights of recent clinically relevant papers

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