AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle
Introduction
Metabolic syndrome is a prevalent disease in both humans and horses (Benamou-Smith, 2007). Insulin resistance (IR) is a key element of equine metabolic syndrome (EMS; Frank et al., 2010). Currently, there is no effective pharmacological treatment for IR and EMS, and studies focusing on identifying effective pharmacological interventions for metabolic diseases are imperative. Recently, considerable interest has been directed at the potential to manipulate 5′-adenosine monophosphate activated protein kinase (AMPK), a fundamental component of cellular energy regulation in mammals (Towler, Hardie, 2007, Hardie, Ashford, 2014). Activation of AMPK by phosphorylation halts ATP consumption and allows regeneration of cellular energy stores (Musi and Goodyear, 2003), so ensuring adequate fuel is available for continual function (Hardie et al, 1998, Fujii et al, 2006). By promoting muscle glucose uptake through insulin-independent processes, AMPK is thought to play an important role in maintaining adequate glucose uptake during cellular stress (Merrill et al, 1997, Fujii et al, 2006). Importantly, down-regulation of AMPK has been implicated in the pathogenesis of IR (Saha et al., 2010).
Glucose uptake into myocytes is mediated by a family of glucose transporters (GLUT) and can occur via insulin-dependent (e.g. phosphatidylinositol 3-kinase) and insulin-independent (e.g. AMPK) pathways (Koistinen and Zierath, 2002). Classic insulin-mediated glucose uptake occurs following translocation of GLUT4 (the major isoform) from an intracellular pool to the cell membrane to facilitate glucose transport, and this pathway dominates in skeletal muscle (Scheepers et al., 2004). However, other isoforms such as GLUT1, a basal GLUT, and novel GLUTs, including GLUT8 have also been shown to participate in glucose uptake in insulin-sensitive tissues (Aerni-Flessner et al., 2012).
Insulin-independent mechanisms for glucose uptake in muscle are an attractive target for therapeutic intervention during insulin insensitivity (Hardie et al., 2012). In line with this, the role of AMPK in carbohydrate metabolism and its associated potential as an effective treatment for metabolic dysfunction has made it the focus of intense research (Hardie et al., 2012). Significantly, an agonist of AMPK, 5′-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been shown to up-regulate glucose uptake in skeletal muscle of humans and rodents (Merrill et al, 1997, Russell et al, 1999), although its role in equine skeletal muscle is unknown. In the current study we hypothesised that AICAR administration would enhance glucose transport in the skeletal muscle of healthy horses through AMPK activation.
Identification of the effect this AMPK agonist has on equine skeletal muscle may not only facilitate an investigation of its potential suitability as a treatment for EMS but also improve our current understanding of insulin-independent mechanisms regulating glucose transport in a species with a unique metabolic profile.
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Subjects
Thoroughbred horses (n = 5; 2 males, 3 females; 6–14 years) were subjected to a thorough physical examination prior to inclusion in the study. The horses were considered to be of moderate body condition (BCS 6 ± 1, weight 554 ± 31 kg). One day before the experiment, horses were brought from pasture into temperature-controlled stalls and remained housed for the duration of the study. Horses were fed grass hay and water ad libitum.
Studies were conducted following protocols approved by the
Results
Upon administration, plasma AICAR concentration reached a Cmax of 32,133 ± 7116 ng/mL between 5 and 10 min, and was rapidly eliminated from plasma (Fig. 1). Mean blood glucose concentration decreased (P <0.05) between 30 and 45 min after the beginning of the AICAR infusion, compared to basal values (Fig. 2A). In contrast, serum insulin concentration increased (P <0.05) at the 10 and 20 min time points, and returned to baseline values within 30 min after the beginning of the AICAR infusion (
Discussion
Despite the marked prevalence of IR and metabolic dysfunction in horses, there is a paucity of data on the role of AMPK in regulating glucose metabolism in this species. This study has provided the first examination of the effect of an AMPK agonist on glucose metabolism in the equine species. The results presented here confirm that AICAR promotes muscle glucose uptake in the horse and suggest that this may be mediated via a novel glucose transporter, GLUT8.
When administered IV in the horse,
Conclusions
Upregulation of the novel glucose transporter, GLUT8, in skeletal muscle following AICAR treatment indicates that an additional active mechanism for glucose uptake exists in the healthy horse. In addition, a dual role for AMPK and insulin in the regulation of blood glucose uptake by AICAR in muscle is possible in the horse, and this premise requires further investigation. Further investigation of the role of AMPK in promoting glucose uptake in skeletal muscle during disease states, such as IR,
Conflict of interest statement
None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.
Acknowledgements
This work was supported by the Oklahoma State Center of Veterinary Sciences Research Funds, the Racing Medication and Testing Consortium, the PA Racing Commissions (# ME 446070), the Pennsylvania Harness Horsemen Association, the Meadows Standardbred Owners Association, and the Pennsylvania Horsemen Benevolent and Protective Association. Technical assistance from Chelsie Clement and Mallika Achanta from Oklahoma State University and from Hilary Goff, Jesse Vanderhoef, Deb Tsang, Susan Megee,
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- 1
These authors contributed equally to this work.
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Current address: Earth, Environmental and Biological Sciences, Queensland University of Technology, Brisbane, Queensland 4001, Australia.