title: Lamellar events related to insulin-like growth factor-1 receptor signalling in two models relevant to endocrinopathic laminitis.
abstract: BACKGROUND
  Insulin dysregulation, obesity, and exposure to high-nonstructural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome-associated laminitis (EMSAL); high systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the insulin-like growth factor-1 receptor.
  
  
  OBJECTIVE
  To use a dietary challenge model (DCM) and a euglycaemic-hyperinsulinaemic clamp (EHC) model to assess lamellar growth factor-related signalling.
  
  
  METHODS
  Lamellar phospho (P)-protein concentrations of signalling proteins important in growth factor-related signalling were assessed in 2 models: 1) lean and obese ponies on a low- or high-NSC diet; and 2) EHC model using Standardbred horses.
  
  
  METHODS
  Ponies stratified for body condition (lean [LN, n = 11] and obese [OB, n = 11]) were exposed to a low-NSC diet (LO, n = 5 per group for LN LO and OB LO) or a high NSC diet (HI, n = 6 per group for LN HI and OB HI groups) for 7 days. For the EHC model, horses were administered insulin (constant rate infusion [6 mIU/kg bwt/min] combined with 50% dextrose, EHC group, n = 8)] or saline (0.57 mL/kg bwt/h, CON group, n = 8) for 48 h. Immunoblotting was employed to assess concentrations of activated/phosphorylated and total protein for members of the PI3K/Akt/mTORC1 and Ras/ERK pathways in lamellar samples from both models.
  
  
  RESULTS
  In the DCM, lamellar P-(Ser 240/244) RPS6 was increased in OB HI ponies (vs. OB LO, P<0.05); positive correlations existed (P<0.05; r>0.5) between Day 7 basal serum insulin concentrations and lamellar concentrations of P-p70S6K and P-(Ser 240/244) RPS6. In the EHC model, lamellar concentrations of P-Akt, P-p70S6K, P-ERK 1/2, P-p90RSK, and both P-(Ser 235/236) and P-(Ser 240/244) RPS6 were increased in the EHC group (vs. CON, P<0.05).
  
  
  CONCLUSIONS
  The primary limitations of this study are the small number of animals per group in the DCM study, and the fact that many animals did not develop laminitis as that was not the endpoint of either study.
  
  
  CONCLUSIONS
  These results support further investigation of mTORC1/RPS6 signalling as a potential therapeutic target(s) in EMSAL. The Summary is available in Chinese - see Supporting Information.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Lane
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Burns
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: O C
authors.initials: OC
authors.lastname: Hegedus
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Watts
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Weber
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Woltman
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Geor
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: McCutcheon
authors.affiliation: Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Eades
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.|Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Mathes
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Belknap
mesh_terms: D000818:Animals; D005534:Foot Diseases / Q000378:metabolism / Q000662:veterinary*; D005786:Gene Expression Regulation; D006724:Hoof and Claw; D006734:Horse Diseases / Q000378:metabolism*; D006736:Horses; D007249:Inflammation; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013002:Somatomedins
chemical_list: D013002:Somatomedins; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1
keywords: equine metabolic syndrome; equine metabolic syndrome-associated laminitis; growth factor signalling; horse; insulin; ribosomal protein S6