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Background  Accumulating evidence suggests that epigenetic changes play key roles in the pathogenesis of type 2 diabetes mellitus (T2DM). However, the dynamic regulation of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in diabetic peripheral blood DNA remains to be elucidated.    Results  We collected fasting blood samples (104 patients and 108 healthy controls) and glucose-stimulated blood samples at different time points (11 patients and 5 healthy controls underwent oral glucose tolerance test (OGTT)), as well as blood samples from six couples of diabetic and control rats. A HPLC-MS/MS system was used for quantifying global 5mC and 5hmC in genomic DNA from white blood cells (WBCs), and qPCR was performed for detecting mRNA expression of  SIRT6  and  TETs . We found that global 5mC decreased, while global 5hmC increased in both patients and diabetic rats, with lower 5mC being a risk factor of T2DM (OR = 0.524, 95%CI 0.402–0.683,  p  = 1.64 × 10 −6 ). The OGTT data from patients showed that 5mC declined within 1 h and then returned to the fasting status at 2 h, while 5hmC rose from 0.5 h to 3 h with increasing glucose. However, the similar patterns were not found in the controls. The mRNA expression of  TET2 ,  TET3 , and  SIRT6  was upregulated in patients ( p  = 0.012,  p  = 0.026, and  p  = 0.035, respectively). The similar results were observed in diabetic OGTT and rats. Correlation analysis indicated that  SIRT6  was positively correlated with  TET2  in humans ( r  = 0.277,  p  < 0.001) and rats ( r  = 0.942,  p  < 0.001), in addition to a correlation between glucose and  SIRT6  ( r  = 0.162,  p  = 0.045) and  TET2  ( r  = 0.174,  p  = 0.036).    Conclusions  Hyperglycemia appeared to promote the mRNA expression of  SIRT6  and  TETs , which in turn might cause the dynamic changes of 5mC and 5hmC in WBCs from T2DM patients.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0660-y) contains supplementary material, which is available to authorized users.

Hyperglycemia affects global 5-methylcytosine and 5-hydroxymethylcytosine in blood genomic DNA through upregulation of SIRT6 and TETs