The pancreatic islet specific microRNA-375 (miR-375) is overexpressed in type 2 diabetes mellitus (T2DM) patients suppressing the glucose-induced insulin secretion. Thus, miR-375 may serve as a biomarker for the early prediction of T2DM among high-risk individuals. We conducted this clinical study to assess the significance of miR-375 among type 2 diabetes mellitus (T2DM) patients and their first-degree relatives.We included 56 Han Chinese individuals (N: NGT = 21, T2DM = 10, FD-NGT =13 and FD-T2DM = 12) who received medical health check-ups from January 2018 to September 2018 at The Third Hospital of Yunnan Province, China. They were categorized as normal glucose tolerance (NGT), T2DM, first-degree relatives with normal glucose tolerance (FD-NGT) and first-degree relatives with T2DM (FD-T2DM). OGTT, C-peptide and Insulin tests were performed to confirm the diagnosis. The miR-375 levels were determined by Quantitative real-time RT-PCR (qRT-PCR).The OGTT test showed a significant difference in T2DM and FD-T2DM groups compared with NGT and FD-NGT (p< 0.05). Similar results were observed during C-peptide and insulin tests. Interestingly, the 2-hour insulin test showed FD-NGT group having a significantly higher mean ± standard error of (64.240 ± 12.775) compared to NGT (28.836 ± 10.875). Assessment of miR-375 expression levels in 4 groups showed a significant up-regulation in T2DM and FD-T2DM compared with NGT and FD-NGT groups. A slight increase in miRNA expression was observed in FD-NGT compared with NGT group but was not statistically significant.The OGTT, C-peptide and insulin tests revealed a statistically significant difference in T2DM and FD-T2DM compared with NGT and FD-NGT groups. A significantly higher miR-375 expression was also observed in T2DM and FD-T2DM groups compared with NGT and FD-NGT and thus, miR-375 may serve as a stable biomarker for the early prediction of T2DM among high-risk individuals.© 2021 Wu et al.