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Randomized Controlled Trial
. 2025 Jan;24(1):e14369.
doi: 10.1111/acel.14369. Epub 2024 Oct 18.

Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes

Steven K Malin  1   2   3   4 , Daniel J Battillo  1 , Michal S Beeri  1 , Maja Mustapic  5 , Francheska Delgado-Peraza  5 , Dimitrios Kapogiannis  5
Affiliations
Randomized Controlled Trial

Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes

Steven K Malin et al. Aging Cell. 2025 Jan.

Abstract

Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m2) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak 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 sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time-points of the OGTT, and levels of insulin signaling proteins (i.e., p-IRS-1, total-/p-Akt, pERK1/2, pJNK1/2, and pp38) and pro-BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60-0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (-0.4 ± 0.9 kg, p = 0.04) and whole-body glucose tAUC120min (p = 0.02). Training lowered 0-min pro-BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, 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/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.

Keywords: aging; glucose tolerance; insulin sensitivity; obesity; physical activity; type 2 diabetes.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Impact of short‐term exercise training on neuronal extracellular vesicle‐derived IRS‐1‐PI3K‐Akt insulin signaling proteins. (a, c, e, and g) represent fasting levels. (b, d, f, and h) represent the change or delta (Δ) of insulin signaling proteins of the OGTT defined as 60 min minus 0 min. Bar graphs represent the mean with individual responses.
FIGURE 2
FIGURE 2
Impact of short‐term exercise training on neuronal extracellular vesicle‐derived Ras‐Mitogen Activated Protein Kinase (MAPK) insulin pathway. (a, c, and e) represent fasting levels. (b, d, and f ) represent the change or delta (Δ) of insulin signaling proteins of the OGTT defined as 60 min minus 0 min. Data were not normally distributed and log transformed for analysis. However, raw data are shown for ease of interpretation. Bar graphs represent mean with individual responses.
FIGURE 3
FIGURE 3
Impact of short‐term exercise training on neuronal extracellular vesicle‐derived pro‐BDNF. Measures were obtained at 0 min of the oral glucose tolerance test (OGTT) and the change in pro‐BDNF following glucose ingestion. The change or delta reflects 60 min minus 0 min of the OGTT. Bar graphs represent the mean with individual responses.
FIGURE 4
FIGURE 4
Correlation of neuronal extracellular vesicle‐derived insulin signaling proteins with peripheral insulin sensitivity.
See this image and copyright information in PMC

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