Aerobic Exercise Training Increases Circulating <scp>sRAGE</scp> in Adults With Type 2 Diabetes: Associations With Sheddase Regulation

OBJECTIVE: Soluble receptor for advanced glycation end-products (sRAGE) and soluble Toll-like receptor 4 (sTLR4) are circulating pattern recognition receptor isoforms implicated in inflammatory regulation in type 2 diabetes mellitus (T2DM). This study examined the effects of supervised aerobic exercise training (AET) on circulating sRAGE, sTLR4, and related skeletal muscle inflammatory signalling outcomes in adults with T2DM. METHODS: ; HbA1c: 6.9% ± 0.9%). Participants in AET completed 12 weeks of supervised aerobic exercise (60 min/day, 5 days/week) at ~70% VO2peak. Pre-and post-intervention assessments included oral glucose tolerance testing, DXA-derived body composition, VO2peak testing, and an acute aerobic exercise trial with blood and skeletal muscle sampling. Circulating sRAGE, sTLR4, hsCRP, and skeletal muscle protein expression of RAGE, TLR2/4, ADAM10, MMP2/9, and TIMP1/3 were quantified. RESULTS: AET increased circulating sRAGE concentrations across the intervention period, whereas sTLR4 was unchanged. AET improved cardiorespiratory fitness, reduced body fat percentage and fat mass, lowered fructosamine concentrations, and increased the Matsuda Index. In skeletal muscle, significant alterations were observed in selected TIMP:MMP and TIMP:ADAM10 ratios, although no changes were detected in ADAM10 activity or skeletal muscle RAGE protein expression. Exploratory analyses demonstrated associations between changes in circulating sRAGE and aerobic fitness. CONCLUSIONS: AET increased circulating sRAGE and improved select metabolic health outcomes in adults with T2DM. These findings are consistent with the concept that chronic exercise training may favourably influence inflammatory regulation in metabolic disease. However, the tissue-specific mechanisms contributing to exercise-induced changes in circulating sRAGE remain incompletely understood and warrant further investigation.