title: Advanced glycation endproducts in horses with insulin-induced laminitis.
abstract: Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of cancer, inflammatory conditions and diabetic complications. An interaction of AGEs with their receptor (RAGE) results in increased release of pro-inflammatory cytokines and reactive oxygen species (ROS), causing damage to susceptible tissues. Laminitis, a debilitating foot condition of horses, occurs in association with endocrine dysfunction and the potential involvement of AGE and RAGE in the pathogenesis of the disease has not been previously investigated. Glucose transport in lamellar tissue is thought to be largely insulin-independent (GLUT-1), which may make the lamellae susceptible to protein glycosylation and oxidative stress during periods of increased glucose metabolism. Archived lamellar tissue from horses with insulin-induced laminitis (n=4), normal control horses (n=4) and horses in the developmental stages (6h, 12h and 24h) of the disease (n=12) was assessed for AGE accumulation and the presence of oxidative protein damage and cellular lipid peroxidation. The equine-specific RAGE gene was identified in lamellar tissue, sequenced and is now available on GenBank. Lamellar glucose transporter (GLUT-1 and GLUT-4) gene expression was assessed quantitatively with qRT-PCR in laminitic and control horses and horses in the mid-developmental time-point (24 h) of the disease. Significant AGE accumulation had occurred by the onset of insulin-induced laminitis (48 h) but not at earlier time-points, or in control horses. Evidence of oxidative stress was not found in any group. The equine-specific RAGE gene was not expressed differently in treated and control animals, nor was the insulin-dependent glucose transporter GLUT-4. However, the glucose transporter GLUT-1 was increased in lamellar tissue in the developmental stages of insulin-induced laminitis compared to control horses and the insulin-independent nature of the lamellae may facilitate AGE formation. However, due to the lack of AGE accumulation during disease development and a failure to detect an increase in ROS or upregulation of RAGE, it appears unlikely that oxidative stress and protein glycosylation play a central role in the pathogenesis of acute, insulin-induced laminitis.
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, Faculty of Science, The University of Queensland, Gatton, Queensland 4343, Australia. m.delaat@uq.edu.au
authors.forename: M A
authors.initials: MA
authors.lastname: de Laat
authors.forename: M T
authors.initials: MT
authors.lastname: Kyaw-Tanner
authors.forename: M N
authors.initials: MN
authors.lastname: Sillence
authors.forename: C M
authors.initials: CM
authors.lastname: McGowan
authors.forename: C C
authors.initials: CC
authors.lastname: Pollitt
mesh_terms: D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis; D005534:Foot Diseases / Q000276:immunology / Q000378:metabolism / Q000662:veterinary*; D005786:Gene Expression Regulation / Q000276:immunology; D051275:Glucose Transporter Type 4 / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000032:analysis*; D006724:Hoof and Claw / Q000737:chemistry* / Q000276:immunology; D006734:Horse Diseases / Q000276:immunology* / Q000378:metabolism; D006736:Horses / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015227:Lipid Peroxidation / Q000276:immunology; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000276:immunology; D016133:Polymerase Chain Reaction / Q000662:veterinary; D017382:Reactive Oxygen Species / Q000032:analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D051275:Glucose Transporter Type 4; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic