BACKGROUND: Single nucleotide polymorphisms (SNPs) in miRNA genes can influence the expression of miRNAs that modulate the PI3K/AKT/GSK3β pathway and play crucial roles in type 2 diabetes mellitus (T2DM) susceptibility. The purpose of this study was to investigate the association of SNPs in miRNA genes targeting the PI3K/AKT/GSK3β pathway with T2DM. METHODS: This case-control study included 1,416 subjects with T2DM and 1,694 non-diabetics. Eleven SNPs in miRNA genes (rs895819 in miR-27a, rs11888095 in miR-128a, rs2292832 in miR-149, rs6502892 in miR-22, rs13283671 in miR-31, rs1076063 and rs1076064 in miR-378a, rs10061133 in miR-449b, rs3746444 in miR-499a and rs678956 and rs476364 in miR-326) involved in PI3K/AKT/GSK3β pathway were genotyped by TaqMan Genotyping Assay, and the associations of these SNPs with T2DM were analyzed using online SHesis and SNPstats. RESULTS: The results showed that miR-378a rs1076064 G allele could be a protective factor against T2DM (p<
0.001, OR=0.828
95% CI:0.749-0.916), whereas the miR-31 rs13283671 C allele could increase the risk of developing T2DM (p=0.003, OR=1.193
95% CI:1.060-1.342). In addition, the miR-378a rs1076063A-rs1076064G haplotype could be a protective against T2DM (p<
0.001, OR=0.731
95% CI:0.649-0.824). According to inheritance mode analysis, compared with the AA-AG genotype, the GG genotype of rs1076064 showed a protective effect in T2DM in the recessive mode (p<
0.01, OR=0.71
95% CI: 0.59-0.84). For rs13283671, compared with the TT genotype, the CT-CC genotype showed a risk effect in T2DM in the dominant inheritance model (p<
0.01, OR=1.29
95% CI: 1.12-1.49). Genotype-Tissue Expression (GTEx) Portal database analysis showed that miR-31 rs13283671 CT and CC genotypes had lower AKT expression than TT genotypes. CONCLUSION: In conclusion, rs13283671 in miR-31 and rs1076064 in miR-378a involved in the PI3K/AKT/GSK3β pathway were associated with T2DM susceptibility in a Chinese population.