Insulin signaling pathway related m6A methylated biomarker for type 2 diabetes and the potential modulation mechanism.

BACKGROUND: Deficiency of insulin signaling components may act as the underlying mechanisms for insulin resistance and type 2 diabetes (T2D). N6-methyladenosine (m6A) is emerging as an important regulatory mechanism in gene expression at the post-transcriptional level. This study aimed to identify the insulin signaling pathway related m6A methylated biomarker for early detection of T2D. METHODS: Candidate genes (PIK3CA and AKT1) with abnormal m6A modification in insulin signaling pathway and the potential methylase (FTO) were selected and validated. Luciferase assay was used to investigate the interaction between FTO and PIK3CA/AKT1. The mechanism of FTO on m6A modification of PIK3CA was validated by methylated RNA immunoprecipitation (MeRIP), western-blot and glucose metabolism assays. The clinical significance of m6A methylated PIK3CA was evaluated in a nested case-control study. RESULTS: We found that the m6A content and mRNA expression of PIK3CA were significantly downregulated and FTO mRNA expression was significantly upregulated in T2D cases and prediabetes, compared with controls. Mechanism analysis demonstrated that FTO overexpression significantly reduced the m6A level, total mRNA and protein expression of PIK3CA, subsequently inhibited glucose consumption and glucose metabolism. m6A methylated PIK3CA can significantly improve the predictive ability of T2D occurrence beyond traditional risk factors alone. CONCLUSION: Decreased m6A level of PIK3CA promote abnormal glucose metabolism and T2D development by reducing PIK3CA mRNA expression, which was under the control of FTO-mediated m6A modification. m6A methylated PIK3CA is a valuable biomarker for prediction and early detection of T2D.