Abstract
The prevalence of type 2 diabetes (T2D) is rapidly increasing across the globe. Fetal exposure to maternal diabetes was correlated with higher prevalence of impaired glucose tolerance and T2D later in life. Previous studies showed aberrant DNA methylation patterns in pancreas of T2D patients. However, the underlying mechanisms remained largely unknown. We utilized human embryonic stem cells (hESC) as the in vitro model for studying the effects of hyperglycemia on DNA methylome and early pancreatic differentiation. Culture in hyperglycemic conditions disturbed the pancreatic lineage potential of hESC, leading to the downregulation of expression of pancreatic markers PDX1, NKX6−1 and NKX6−2 after in vitro differentiation. Genome-wide DNA methylome profiling revealed over 2000 differentially methylated CpG sites in hESC cultured in hyperglycemic condition when compared with those in control glucose condition. Gene ontology analysis also revealed that the hypermethylated genes were enriched in cell fate commitment. Among them, NKX6−2 was validated and its hypermethylation status was maintained upon differentiation into pancreatic progenitor cells. We also established mouse ESC lines at both physiological glucose level (PG-mESC) and conventional hyperglycemia glucose level (HG-mESC). Concordantly, DNA methylome analysis revealed the enrichment of hypermethylated genes related to cell differentiation in HG-mESC, including Nkx6−1. Our results suggested that hyperglycemia dysregulated the epigenome at early fetal development, possibly leading to impaired pancreatic development.
Highlights
We demonstrated that hyperglycemia during early pancreatic differentiation of human embryonic stem cells (hESC) disrupted the histone methylation of key pancreatic markers, leading to the impairment of pancreatic progenitor differentiation [16]
HESC with prior exposure to hyperglycemic conditions exhibited disrupted pancreatic differentiation even when differentiation was induced at a conventional glucose level
The results revealed a critical concept that transient high glucose exposure in embryos was sufficient for epigenetic dysregulation, pre-disposing to defects in subsequent pancreatic differentiation and development
Summary
It was estimated that over 400 million patients were suffering from diabetes and the global prevalence of diabetes and impaired glucose tolerance would reach over 500 million in 20 years [1]. Type 2 diabetes (T2D) accounts for around 90% of the diabetic cases. Lifestyle and genetics are the two major risk factors leading to the disease. The in-utero environment, which plays a pivotal role in fetal development, is considered as another risk factor for T2D development in offspring. The concept of “Developmental origins of health and disease” has long been proposed, stating that alterations in the fetal environment had consequences in postnatal life, including later onset of non-communicable diseases [2,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
