title: Prolonged hyperinsulinemia affects metabolic signal transduction markers in a tissue specific manner.
abstract: Insulin dysregulation is common in horses although the mechanisms of metabolic dysfunction are poorly understood. We hypothesized that insulin signaling in striated (cardiac and skeletal) muscle and lamellae may be mediated through different receptors as a result of receptor content, and that transcriptional regulation of downstream signal transduction and glucose transport may also differ between tissues sites during hyperinsulinemia. Archived samples from horses treated with a prolonged insulin infusion or a balanced electrolyte solution were used. All treated horses developed marked hyperinsulinemia and clinical laminitis. Protein expression was compared across tissues for the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) by immunoblotting. Gene expression of metabolic insulin-signaling markers (insulin receptor substrate 1, Akt2, and glycogen synthase kinase 3 beta [GSK-3β]) and glucose transport (basal glucose transporter 1 and insulin-sensitive glucose transporter 4) was evaluated using real-time reverse transcription polymerase chain reaction. Lamellar tissue contained significantly more IGF-1R protein than skeletal muscle, indicating the potential significance of IGF-1R signaling for this tissue. Gene expression of the selected markers of insulin signaling and glucose transport in skeletal muscle and lamellar tissues was unaffected by prolonged hyperinsulinemia. In contrast, the significant upregulation of Akt2, GSK-3β, GLUT1, and GLUT4 gene expression in cardiac tissue suggested that the prolonged hyperinsulinemia induced an increase in insulin sensitivity and a transcriptional activation of glucose transport. Responses to insulin are tissue-specific, and extrapolation of data across tissue sites is inappropriate.
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: A
authors.initials: A
authors.lastname: Campolo
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: de Laat
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: L
authors.initials: L
authors.lastname: Keith
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Gruntmeir
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA. Electronic address: veronique.lacombe@okstate.edu.
authors.forename: V A
authors.initials: VA
authors.lastname: Lacombe
mesh_terms: D000818:Animals; D015415:Biomarkers; D006734:Horse Diseases / Q000139:chemically induced* / Q000378:metabolism; D006736:Horses / Q000097:blood / Q000502:physiology*; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000662:veterinary*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D007328:Insulin
keywords: Glucose transporter; Horse; Insulin receptor; Insulin signaling; Laminitis