Type 2 diabetes (T2D) is associated with poor bone quality and bone fragility, independently of bone mineral density (BMD). Circulating miRNAs have been suggested to play a role in diabetic bone disease. Appropriate exercise results in bone mass maintenance, bone formation and improved bone strength. Exercise-associated modulation of miRNA levels may mediate these effects. This study was aimed at testing the hypothesis that exercise training might be associated with different expression of specific miRNAs involved in bone metabolism in T2D. To this end, 15 trained (T) and 15 untrained (UT) people with T2D were randomly selected from participants in the SWEET BONE Trial at the end of the 2-year exercise intervention. A screening analysis of the entire miRNome was performed by Next Generation Sequencing (NGS). Relevant up/down-regulated miRNAs were tested and validated by quantitative Real Time-PCR (RT-PCR). Groups did not differ in terms of age, diabetes duration, glycemic control and BMI. There were 8 female participants (53%) per group. The T group showed higher levels of physical activity and physical performance, compared to UT (SPPB score 11.3±1.0 vs 9.9±2.1, p=0.033). Among the measured bone turnover markers, PINP resulted significantly higher T compared to UT (241.8±86.8 vs 176.3±51.3 pg/ml, p=0.018). NGS analysis evidenced up-regulation and down-regulation of several miRNAs in T and UT patients’ sera. Among these, miR-378a was significantly down-regulated in T vs UT (p<0.000). Quantitative RT-PCR validation confirmed miR-378a to be 30% lower in the trained T2D. In conclusion, exercise training is associated with miR-378a down-regulation and the increase of PINP. Previous studies showed that (1) miR-378a might mediate bone metabolism and bone development, whereas its suppression favors osteogenesis (Feng L. et al Molecular Therapy: Nucleic Acids Vol. 21, 2020); and (2) exercise-is associated with an increase of PINP, a known marker of bone formation (Dolan E et al. Exerc. Sport Sci. Rev. 2020; 48(2): 49-58). Therefore, we can speculate that miR-378a might be one of the signature miRNAs responsible for the positive effect of exercise training on bone metabolism in T2D.