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.sub.I) was estimated using a mathematical model. Results Exenatide resulted in a postprandial decrease of 20% (effect size: 2673 [micro]U*min/ml; 95% CI: 900 - 4446 [micro]U*min/ml; P = 0.003) in AUC of plasma insulin (control; mean AUC insulin: 11,989 [micro]U*min/ml; 95% CI: 9673 - 14,305 [micro]U*min/ml, exenatide; mean AUC insulin: 9316 [micro]U*min/ml; 95% CI: 7430 - 11,202 [micro]U*min/ml). Exenatide resulted in an approximately threefold increase (effect size: 5.56 10.sup.-4* [micro]U/ml.sup.-1*min.sup.-1; 95% CI: 0.95 - 10.1 10.sup.-4* [micro]U/ml.sup.-1*min.sup.-1; P = 0.02) in estimated insulin sensitivity (control mean S.sub.I: 1.93 10.sup.-4* [micro]U/ml.sup.-1*min.sup.-1; 95% CI: 0.005 - 3.86 10.sup.-4*[micro]U/ml.sup.-1*min.sup.-1 vs. exenatide mean S.sub.I: 7.49 10.sup.-4* [micro]U/ml.sup.-1*min.sup.-1; 95% CI: 3.46 - 11.52 10.sup.-4* [micro]U/ml.sup.-1*min.sup.-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. Keywords: Horse, Insulin dysregulation, Insulin sensitivity, Equine Metabolic Syndrome (EMS), Insulin secretion