Effect of a GLP-1 mimetic on the insulin response to oral sugar testing in horses

BACKGROUND: Insulin dysregulation (ID) is the most important risk factor for the development of laminitis in horses and therapies to control it are needed. HYPOTHESIS/OBJECTIVES: To assess the effects of a single dose of the synthetic GLP-1 analog exenatide on postprandial insulin dynamics. We hypothesized that exenatide would improve insulin sensitivity and lower postprandial blood insulin concentrations. STUDY DESIGN: Randomized, crossover, experimental study. ANIMALS: Six horses (3 mares, 3 geldings; 2 with normal insulin regulation [NIR] and 4 with mild ID). METHODS: Horses completed both study arms: subcutaneous administration of exenatide (or no treatment) 30 min before an oral sugar test (0.15 ml/kg of Karo Syrup). Blood samples obtained over 240 min were assayed for glucose, insulin, lactate, c-peptide and total GLP-1. The area under the curve (AUC) was calculated using the trapezoidal rule. Insulin sensitivity (S(I)) was estimated using a mathematical model. RESULTS: Exenatide resulted in a postprandial decrease of 20% (effect size: 2673 µU·min/ml; 95% CI: 900 – 4446 µU·min/ml; P = 0.003) in AUC of plasma insulin (control; mean AUC insulin: 11,989 µU·min/ml; 95% CI: 9673 – 14,305 µU·min/ml, exenatide; mean AUC insulin: 9316 µU·min/ml; 95% CI: 7430 – 11,202 µU·min/ml). Exenatide resulted in an approximately threefold increase (effect size: 5.56 10(–4)· µU/ml(−1)·min(−1); 95% CI: 0.95 – 10.1 10(–4)· µU/ml(−1)·min(−1); P = 0.02) in estimated insulin sensitivity (control mean S(I): 1.93 10(–4)· µU/ml(−1)·min(−1); 95% CI: 0.005 – 3.86 10(–4)·µU/ml(−1)·min(−1) vs. exenatide mean S(I): 7.49 10(–4)· µU/ml(−1)·min(−1); 95% CI: 3.46 – 11.52 10(–4)· µU/ml(−1)·min(−1)). CONCLUSIONS: The decrease in insulin response to carbohydrates was due to an increase in whole-body insulin sensitivity. GLP-1 agonists may have therapeutic potential for ID in horses.