Yang Kun, Sun Juan, Zhang Zijie, Xiao Mengyao, Ren Decheng, Liu Song-Mei
Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China.
Department of Neurobiology, The University of Chicago, 5841, S. Maryland Avenue, MC 1027, Chicago, IL 60637, USA.
Diabetes Res Clin Pract. 2023 Apr;198:110607. doi: 10.1016/j.diabres.2023.110607. Epub 2023 Mar 4.
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).
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.
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.
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.
信使核糖核酸（mRNA）中的N - 甲基腺苷（mA）参与葡萄糖代谢。我们的目标是研究在2型糖尿病（T2D）发生发展过程中，葡萄糖代谢、mA以及与mA结合的含YTH结构域蛋白1（YTHDC1）之间的关系。
采用高效液相色谱 - 串联质谱法（HPLC - MS/MS）和定量逆转录聚合酶链反应（qRT - PCR）来测定T2D患者和健康个体白细胞中mA和YTHDC1的水平。利用MIP - CreERT和他莫昔芬处理构建β细胞Ythdc1基因敲除小鼠（βKO）。对野生型/βKO胰岛和MIN6细胞进行mA测序和RNA测序，以鉴定差异基因。
在T2D患者中，mA和YTHDC1水平均降低，且与空腹血糖相关。Ythdc1的缺失导致葡萄糖不耐受和糖尿病，原因是胰岛素分泌减少，尽管βKO小鼠的β细胞量与野生型小鼠相当。此外，在β细胞中，Ythdc1被证明与富含丝氨酸/精氨酸的剪接因子3（SRSF3）和切割及聚腺苷酸化特异性因子6（CPSF6）结合。
我们的数据表明，YTHDC1可能通过与SRSF3和CPSF6相互作用来调节mRNA剪接和输出，进而通过调节胰岛素分泌来调控葡萄糖代谢，这意味着YTHDC1可能是降低血糖的一个新的潜在靶点。
