The potential of circulating free DNA of methylated IGFBP as a biomarker for type 2 diabetes Mellitus: A Comprehensive review.

T2DM detection methods are commonly used in teens and adults but are generally unsuitable to unborn fetuses in the context of non-invasive prenatal testing (NIPT). Biophysical and biochemical tests for fetuses are often invasive, carry risks, and have low sensitivity and specificity, with no direct method available to diagnose T2DM in utero. In contrast, cell-free DNA (cfDNA) is known have high sensitivity (93-98 %) and specificity (94-100 %) for cancer detection and fetal genetic disorders (trisomy 21, 8, and 13) making it applicable for fetal epigenetic and genetic analysis, including T2DM early detection. However, no study has explored its use for this purpose. Our review focuses on the potential of IGFBP methylation levels in cfDNA as biomarkers for NIPT of T2DM. Placental global hypomethylation in GDM may predict T2DM during the prenatal period, and a similar pattern potentially be detected in cfDNA. Targeted genes reliable for NIPT, such as IGFBPs are needed because their significant role in T2DM and GDM. Among these, IGFBP-1 and IGFBP-2 have shown potential as predictive genes, exhibiting hypermethylation in placental tissue from GDM cases. This hypermethylation reduces their expression and the formation of the IGF-1-IGFBP complex, leading to increased levels of free IGF-1, which is associated with T2DM in the fetus. Hypermethylation regions have longer fragment sizes in cfDNA, thus in T2DM cases, hypermethylation of IGFBP-1 and IGFBP-2 from fetus results in longer cfDNA fragments. Therefore, analyzing the methylation levels and fragment sizes of IGFBP-1 or IGFBP-2 cfDNA could be a promising biomarker for identifying fetal T2DM risk non-invasively.