Abstract
Genome-wide association study (GWAS) data showed that the protein tyrosine phosphatase receptor type delta (PTPRD) is associated with increased susceptibility to type 2 diabetes (T2D) in Han Chinese. A replication study indicated that PTPRD is involved in the insulin signaling pathway; however, the underlying mechanism remains unclear. We evaluated PTPRD expression in patients with T2D and controls. PTPRD expression levels were lower in patients and were correlated with the duration of the disease. Overexpression of the human insulin receptor PPARγ2 in HepG2 cells induced overexpression of PTPRD and the insulin receptor. PTPRD knockdown, using a shRNA, resulted in down-regulation of the insulin receptor. These results indicate that PTPRD activates PPARγ2 in the insulin signaling pathway. Similar results for PTPRD expression were found using a T2D mouse model. Silencing of PTPRD was caused by DNA methylation in T2D mice and patients, and correlated with DNMT1 expression. Furthermore, we showed that a DNMT1 SNP (rs78789647) was correlated with susceptibility to T2D. This study shows for the first time that DNMT1 caused PTPRD DNA hypermethylation and induced insulin signaling silencing in T2D patients. Our findings contribute to a better understanding of the crucial roles of these regulatory elements in human T2D.
Highlights
Type 2 diabetes (T2D) is a complex disorder that is characterized by hyperglycemia, caused by impaired pancreatic β-cell function, decreased insulin action, and increased glucose output by the liver [1,2,3]
Genome-wide association study (GWAS) data previously indicated that phosphatase receptor type delta (PTPRD) is involved in T2D
We showed that PTPRD mRNA levels were lower in patients with T2D and that they were correlated with disease progression
Summary
Type 2 diabetes (T2D) is a complex disorder that is characterized by hyperglycemia, caused by impaired pancreatic β-cell function, decreased insulin action, and increased glucose output by the liver [1,2,3]. Both genetic and environmental factors contribute to the pathogenesis of T2D [4]. The PTPRD genetic variant was suggested to be associated with progression to diabetes in Han Chinese, most likely through enhanced insulin resistance [13]. Until now, the exact roles of epigenetic factors and PTPRD in T2D onset and development remain unclear
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