25-OR: Two Weeks of Exercise Alters Neuronal Extracellular Vesicle Insulin Signaling in Adults with Prediabetes

Introduction & Objective: Prediabetes raises Alzheimer’s Disease and Related Dementia (ADRD) risk. While exercise may lower ADRD risk, it is unclear if it does so by raising brain insulin sensitivity and/or brain derived neurotrophic growth factor (BDNF). We hypothesized that short-term exercise would raise brain insulin signaling and BDNF from neuronal extracellular vesicles (nEVs) in adults with prediabetes.

Methods: Twenty-one adults (18F, 60.0±8.6 y; 33.5±1.1 kg/m²) with prediabetes (75g OGTT, ADA criteria) were randomized to 12 supervised work-matched continuous (n=13, 70% HR_peak) or interval (n=8, 90% and 50% HR_peak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO₂peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin resistance (glucose x insulin tAUC) were determined from a 120min 75g OGTT. nEVs were measured at 0- and 60min of the OGTT to depict phosphorylated insulin signaling (i.e. p-IRS-1, total/pAkt, pERK1/2, pJNK1/2 and pp38) and pro-BNDF. OGTT stimulated effects were calculated from protein differences (i.e. 60-0min).

Results: Adults were collapsed into a single group as exercise intensity did not affect measures. Exercise raised VO₂peak (+1.4±2.0 ml/kg/min, P<0.01) and decreased weight (-0.4±0.9 kg, P=0.04) as well as whole-body glucose tAUC_120min (P=0.02) and insulin resistance (P=0.01). Training lowered fasting pro-BDNF (704.1±1019.0 vs. 414.5±533.5 pg/ml, P=0.04), and increased OGTT-stimulated tAkt (-51.8±147.2 vs. 95±204.5 a.u., P=0.01), which was paralleled by reduced pAkt/total-Akt at 60min of the OGTT (1.3±0.2 vs. 1.2±0.1 a.u., P=0.04). No other insulin protein was impacted by exercise.

Conclusion: Two weeks of exercise altered brain insulin signaling responses to the OGTT and lowered pro-BNDF in adults with prediabetes. Further work is needed to assess if exercise-induced brain insulin sensitivity contributes to ADRD risk reduction.