Abstract
BackgroundEquine metabolic syndrome (EMS) is associated with insulin dysregulation, which often manifests as post-prandial hyperinsulinemia. Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP-1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. However, little is known about the equine GLP-1 receptor (eGLP-1R), or whether GLP-1 concentrations can be manipulated. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated.MethodsArchived and abattoir-sourced tissues from healthy horses were used. Reverse transcriptase PCR was used to determine the tissue distribution of the eGLP-1R gene, with immunohistochemical confirmation of its pancreatic location. The GLP-1 secretion from intestinal explants in response to 4 and 12 mM glucose was quantified in vitro. Pancreatic islets were freshly isolated to assess the insulin secretory response to GLP-1 agonism and antagonism in vitro, using concentration-response experiments.ResultsThe eGLP-1R gene is widely distributed in horses (pancreas, heart, liver, kidney, duodenum, digital lamellae, tongue and gluteal skeletal muscle). Within the pancreas the eGLP-1R was immunolocalised to the pancreatic islets. Insulin secretion from pancreatic islets was concentration-dependent with human GLP-1, but not the synthetic analogue exendin-4. The GLP-1R antagonist exendin 9-39 (1 nM) reduced (P = 0.08) insulin secretion by 27%.DiscussionThe distribution of the eGLP-1R across a range of tissues indicates that it may have functions beyond insulin release. The ability to reduce insulin secretion, and therefore hyperinsulinemia, through eGLP-1R antagonism is a promising and novel approach to managing equine insulin dysregulation.
Highlights
Hyperinsulinemia can cause digital lamellar failure, which results in laminitis in horses (de Laat et al, 2010)
Despite data in vivo suggesting that a functional glucagon-like peptide-1 (GLP-1) receptor exists in horses, the current study is the first to demonstrate the location/s of the equine GLP-1 receptor (eGLP-1R)
As is the case in other species, where the GLP-1 receptor is highly expressed on the β-cells of the pancreatic islets (Doyle & Egan, 2007; Holst, 2007), the eGLP-1R was immunolocalised within the islets of the pancreas
Summary
Hyperinsulinemia can cause digital lamellar failure, which results in laminitis in horses (de Laat et al, 2010). The drivers for post-prandial hyperinsulinemia in horses are incompletely understood, but incretin hormone concentrations positively correlate with an increased insulin response to carbohydrate intake in predisposed breeds (Bamford et al, 2015). Circulating concentrations of the principal incretin hormone, glucagon-like peptide-1 (GLP-1), are lower in horses, than humans, as is their capacity to supplement post-prandial insulin secretion (Chameroy et al, 2016; Wu, Rayner & Horowitz, 2016). Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP-1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated. The ability to reduce insulin secretion, and hyperinsulinemia, through eGLP-1R antagonism is a promising and novel approach to managing equine insulin dysregulation
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