Genomic and Transcriptomic Variations of INSR Are Associated With Dysregulation of Circulatory miRNA-21 and miRNA-146a in Type 2 Diabetes Mellitus.

BACKGROUND

This cross-sectional case-control study aimed to investigate the association between germline and sporadic variations in the Insulin Receptor (INSR) gene, risk factors, and the differential expression of circulating miRNA-21 and miRNA-146a in the onset of Type 2 diabetes mellitus (T2DM).

METHOD: A total of 800 T2DM patients and 600 nondiabetic age- and gender-matched individuals participated in single nucleotide polymorphism (SNPs) screening in the INSR gene via polymerase chain reaction (PCR), followed by Sanger sequencing. Transcriptional expression was quantified using reverse transcriptase PCR (RT-PCR). Relative expression levels of circulating miRNAs were determined by real-time PCR.

RESULTS

A significant (p < 0.05) association of Exon 17 INSR SNPs with T2DM, including a single base substitution mutation at Codon 115 (rs1799817; CAC > CAT) and Codon 83 (rs1799816; GGT > GAT), was found. However, a deletion mutation at Codon 186 (rs1052371; delT) showed no significant association with the disease. Linkage disequilibrium analysis (r 2 > 0.8) indicated a strong correlation among these SNPs and T2DM. INSR and miRNA-21 levels were significantly downregulated in T2DM patients, while circulating miRNA-146a was upregulated, as shown by relative expression analysis. ROC curve analysis indicated that miRNA-21 and miRNA-146a exhibited high diagnostic efficacy for T2DM. Furthermore, combined detection of these miRNAs showed greater potential as biomarkers for insulin resistance and metabolic complications in T2DM, particularly in this study population.

CONCLUSION

This study highlights a significant association between SNPs in Exon 17 of INSR and the differential expression of circulating miRNAs in T2DM.