Abstract
Differential DNA methylation with hyperglycemia is significantly associated with Type 2 Diabetes (T2D). Longtime extended exposure to high blood glucose levels can affect the epigenetic signatures in all organs. However, the relevance of the differential DNA methylation changes with hyperglycemia in blood with pancreatic islets remains unclear. We investigated differential DNA methylation in relation to glucose homeostasis based on the Oral Glucose Tolerance Test (OGTT) in a population-based cohort. We found a total of 382 differential methylation sites from blood DNA in hyperglycemia and type 2 diabetes subgroups using a longitudinal and cross-sectional approach. Among them, three CpG sites were overlapped; they were mapped to the MSI2 and CXXC4 genes. In a DNA methylation replication study done by pyrosequencing (n = 440), the CpG site of MSI2 were shown to have strong associations with the T2D group (p value = 2.20E-16). The differential methylation of MSI2 at chr17:55484635 was associated with diabetes-related traits, in particular with insulin sensitivity (QUICKI, p value = 2.20E-16) and resistance (HOMA-IR, p value = 1.177E-07). In human pancreatic islets, at the single-base resolution (using whole-genome bisulfite sequencing), the 292 CpG sites in the ±5kb at chr17:55484635 were found to be significantly hypo-methylated in donors with T2D (average decrease = 13.91%, 95% confidence interval (CI) = 4.18~ 17.06) as compared to controls, and methylation patterns differed by sex (-9.57%, CI = -16.76~ -6.89) and age (0.12%, CI = -11.17~ 3.77). Differential methylation of the MSI2 gene (chr17:55484635) in blood and islet cells is strongly related to hyperglycemia. Our findings suggest that epigenetic perturbation on the target site of MSI2 gene in circulating blood and pancreatic islets should represent or affect hyperglycemia.
Highlights
Epigenetics is the main mechanism that mediates the effects of dietary and lifestyle factors [1]
We found that differential methylation of the MSI2 gene in blood was strongly correlated with glycemic traits, and differential methylation was found in pancreatic islets from donors with type 2 diabetes
We aimed to identify a differential methylation profile of peripheral blood related to hyperglycemia
Summary
Epigenetics is the main mechanism that mediates the effects of dietary and lifestyle factors [1]. Lifestyle factors such as diet, tobacco smoking, alcohol consumption, and exposure to environmental pollutants can modify epigenetic patterns [2,3,4,5]. Glucose levels are maintained by pancreatic hormones to maintain blood glucose homeostasis within a normal range. Glucose levels increase and decrease in healthy people; this may not be the case in people with type 2 diabetes (T2D). Postprandial hyperglycemia is known to be one of the earliest.
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