Saxagliptin: a doping agent? Inhibition of NPY1-36 cleavage improves cycling performance

Introduction - Neuropeptides Y (NPYs) contribute to the adreno-sympathetic stimulation, NPY1-36 potentiates catecholamines (CATs) effects whilst NPY3-36 inhibits CATs’ release.

Objectives - Investigate whether inhibiting dipeptidyl-peptidase-4 (DPP4), the main enzyme cleaving NPY1-36 into NPY3-36 increases NPY1-36 potentiating effects and reduces NPY3-36 inhibiting effects on CATs; thereby leading to performance improvement.

Methods - Seven participants performed a time-to-exhaustion cycling exercise at 95% of peak power output under either placebo (pcb) or saxagliptin (gpt), a DPP4 inhibitor, per os. Oxygen consumption (V̇O2), heart rate variability, NPY1-36, NPY3-36, catecholamines and lactate were measured at several time points before, during, and after exercise.

Results - DPP4 activity (12.7 ± 1.6 vs. 0.2 ± 0.3 U/L) and NPY3-36 (1.94 ± 0.88 vs. 0.73 ± 0.22 pM) decreased at rest in gpt whilst NPY1-36 increased (2.64 ± 2.22 vs. 4.59 ± 2.98 pM) and CATs was unchanged. Time-to-exhaustion was 32% higher in gpt, and pcb-to-gpt increase in time-to-exhaustion was correlated to NPY1-36 changes (R=0.78, p<0.05). Peak V̇O2 values were not different whilst there was a tendency for peak lactate to be higher and peak NPYs concentrations were higher in gpt. Exercise and post-exercise kinetics in all parameters were not different.

Discussion - DPP4 blockade increased NPY1-36 and decreased NPY3-36 concentrations which resulted in an increased potentiating effect on CATs and was likely responsible for performance improvement. Future studies need to determine the specific effects of NPYs and incretins on skeletal and myocardial muscles and establish whether DPP4 inhibitors could be a new class of doping agents.