title: AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.
abstract: Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation.
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: de Laat
authors.affiliation: Penn Vet Equine Pharmacology Laboratory, Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Robinson
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Gruntmeir
authors.affiliation: Penn Vet Equine Pharmacology Laboratory, Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Penn Vet Equine Pharmacology Laboratory, Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, PA, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Soma
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA. Electronic address: veronique.lacombe@okstate.edu.
authors.forename: V A
authors.initials: VA
authors.lastname: Lacombe
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D005260:Female; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D006736:Horses; D007328:Insulin / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AMPK; Equine metabolic syndrome; GLUT; Horse; Insulin resistance