Abstract：
Homocysteine (Hcy) is a sulfur-containing amino acid. An elevated level of Hcy is a risk factor for diabetes development. However, the mechanism of its effect on pancreatic β-cell function is unclear. In this study, we constructed a hyperhomocysteinemia (HHcy) mouse model by feeding mice a high methionine diet (HMD). The mice suffered impaired glucose tolerance and reduced insulin secretion. Furthermore, at the cellular level, INS1 cells exhibited impaired insulin secretory function after the Hcy intervention. Transcriptomics revealed that Zbtb20 expression was downregulated and the downstream gene Fbp1 was upregulated in HHcy-induced mice compared with mice fed with normal diet. Insulin secretion could be restored by Zbtb20 overexpression or fructose 1,6-bisphosphatase (FBPase) activity inhibition in INS1 cells. In conclusion, our study suggested that Hcy inhibited the insulin secretory function of pancreatic β-cells by suppressing Zbtb20 expression, leading to the development of diabetes. Zbtb20 may be a key target in the development of diabetes associated with elevated Hcy levels.
摘要：
同型半胱氨酸(Hcy)是含硫氨基酸。Hcy水平升高是糖尿病发展的危险因素。然而,其对胰岛β细胞功能的影响机制尚不清楚。在这项研究中,我们通过给小鼠喂食高蛋氨酸饮食（HMD）来构建高同型半胱氨酸血症（HHcy）小鼠模型。小鼠的葡萄糖耐量受损，胰岛素分泌减少。此外，在细胞水平上，Hcy干预后，INS1细胞表现出胰岛素分泌功能受损。转录组学显示，与正常饮食的小鼠相比，HHcy诱导的小鼠中Zbtb20表达下调，下游基因Fbp1上调。胰岛素分泌可以通过Zbtb20过表达或抑制INS1细胞中的果糖1,6-双磷酸酶（FBPase）活性来恢复。总之,我们的研究表明，Hcy通过抑制Zbtb20的表达来抑制胰岛β细胞的胰岛素分泌功能，导致糖尿病的发展。Zbtb20可能是与Hcy水平升高相关的糖尿病发展的关键靶标。
