Sweet taste receptor inhibitors: Potential treatment for equine insulin dysregulation

Hyperinsulinemia is a major risk factor for equine laminitis, a debilitating and painful foot condition. Sweet taste receptor (T1R2/3) inhibitors have been used to reduce the insulin and glucose responses to oral carbohydrates in other species. However, their effect in horses has not been investigated. It would be useful to be able to attenuate the large post-prandial insulin response that typically occurs when a carbohydrate-rich meal is fed to insulin-dysregulated horses. Here we have determined the efficacy of two T1R2/3 inhibitors, lactisole and Gymnema sylvestre, for reducing glucose uptake by the equine small intestine in vitro; and post-prandial insulin secretion in ponies in vivo, following a carbohydrate-based meal. We used gas chromatography-mass spectrometry to measure 2-deoxyglucose uptake by explants of small intestine, in the presence and absence of the T1R2/3 inhibitors. Lactisole and G sylvestre reduced 2-deoxyglucose uptake by the intestinal explants by 63% (P = 0.032) and 73% (P = 0.047), respectively, compared to control samples. The study in vivo investigated the effect of the inhibitors on the blood glucose and serum insulin responses to a meal containing D-glucose. Three doses of each inhibitor were tested using a Latin square design, and each dose was compared to a meal with no inhibitor added. Lactisole had no effect on glucose and insulin concentrations, whereas G sylvestre was partially effective at reducing post-prandial blood glucose (by ~10%) and serum insulin concentrations (~25%) in seven ponies, with a most effective dose of 10 mg/kg bodyweight. These data provide preliminary support that T1R2/3 inhibitors may be a useful therapeutic strategy for the management of equine insulin dysregulation and the prevention of laminitis. However, further optimisation of the dose and delivery method for these compounds is required, as well as a direct investigation of their activity on the equine sweet taste receptor