Reduction of mRNA mA associates with glucose metabolism via YTHDC1 in human and mice.

Aims: N-methyladenosine (mA) in mRNA is involved in glucose metabolism. Our goal is to investigate the relationship of glucose metabolism, mA and YTH domain-containing protein 1 (YTHDC1), a binding protein to mA, in the development of type 2 diabetes (T2D).

Methods: HPLC-MS/MS and qRT-PCR were used to quantify mA and YTHDC1 levels in white blood cells from patients with T2D and healthy individuals. MIP-CreERT and tamoxifen treatment were used to create β-cell Ythdc1 knockout mice (βKO). mA sequencing and RNA sequencing were performed in wildtype/βKO islets and MIN6 cells to identify the differential genes.

Results: In T2D patients, both of mA and YTHDC1 levels were reduced and associated with fasting glucose. Deletion of Ythdc1 resulted in glucose intolerance and diabetes due to decreased insulin secretion, even though β-cell mass in βKO mice was comparable to wildtype mice. Moreover, Ythdc1 was shown to bind to SRSF3 (serine/arginine-rich splicing factor 3) and CPSF6 (cleavage and polyadenylation specific factor 6) in β-cells.

Conclusions: Our data suggested that YTHDC1 may regulate mRNA splicing and export by interacting with SRSF3 and CPSF6 to modulate glucose metabolism via regulating insulin secretion, implying YTHDC1 might be a novel potential target for lowing glucose.