Single aerobic exercise bout shows mixed effects on glucose and neuronal insulin signaling in obesity

UNLABELLED: Exercise may lower Alzheimer's Disease and Related Dementia (ADRD) risk. While insulin has been proposed to benefit cognition, the effect of exercise on neuronal insulin signaling in humans is unclear. PURPOSE: We tested the hypothesis that a single bout of aerobic exercise would raise insulin signaling mediators from plasma-derived neuronal extracellular vesicles (nEVs). METHODS: Fifteen sedentary adults with obesity (12F; ~56y; ~31 kg/m) completed an evening rest and acute exercise condition (70% maximal oxygen consumption (VOmax)) in a randomized, counterbalanced order. Following an overnight fast, plasma was collected for analysis of nEV insulin signaling biomarkers before and after intranasal insulin spray (INI, 40 IU) as well as 60 min following a 75 g oral glucose tolerance test (OGTT). Plasma glucose and insulin were also measured at 30 and 60 min during the OGTT, and total area under the curve (tAUC) was calculated. RESULTS: Exercise tended to lower glucose tAUC (p = 0.08, d = 0.50), independent of insulin tAUC (p = 0.99, d = 0.00). Exercise increased pIR-Tyr1162/Tyr1163 (p = 0.05, η = 0.05), pIRS-1-Ser636 (p = 0.02, η = 0.07), pAkt-Ser473 (p = 0.03, η = 0.06), and pTSC2-Ser939 (p = 0.01, η = 0.08) with medium effect sizes across blood draws, compared with the resting condition. Exercise also raised fasting and decreased pp70S6K-Thr412 before and after the OGTT, compared with increased levels after rest during the OGTT (p = 0.02, η = 0.10). Exercise had no effect on other insulin signaling proteins (e.g., pmTOR-Ser2448, pGSK3β-Ser9, etc.). CONCLUSIONS: A single bout of aerobic exercise increases some nEV-associated insulin signaling phosphoproteins in people with cardiometabolic risk. Additional work is warranted to determine if changes in brain insulin signaling translate to lower ADRD risk. CLINICAL TRIALS REGISTRATION: NCT05853913.