Type 2 diabetes (T2D) is a complex disease characterised by chronic hyperglycaemia. The effects of elevated glucose on global gene expression in combination with DNA methylation patterns have not yet been studied in human pancreatic islets. Our aim was to study the impact of 48 h exposure to high (19 mM) versus control (5.6 mM) glucose levels on glucose-stimulated insulin secretion, gene expression and DNA methylation in human pancreatic islets.

While islets kept at 5.6 mM glucose secreted significantly more insulin in response to short term glucose-stimulation (p = 0.0067), islets exposed to high glucose for 48 h were desensitised and unresponsive to short term glucose-stimulation with respect to insulin secretion (p = 0.32). Moreover, the exposure of human islets to 19 mM glucose resulted in significantly altered expression of eight genes (FDR<5%), with five of these (GLRA1, RASD1, VAC14, SLCO5A1, CHRNA5) also exhibiting changes in DNA methylation (p < 0.05). A gene set enrichment analysis of the expression data showed significant enrichment of e.g. TGF-beta signalling pathway, Notch signalling pathway and SNARE interactions in vesicular transport; these pathways are of relevance for islet function and possibly also diabetes. We also found increased DNA methylation of CpG sites annotated to PDX1 in human islets exposed to 19 mM glucose for 48 h. Finally, we could functionally validate a role for Glra1 in insulin secretion.

Our data demonstrate that high glucose levels affect human pancreatic islet gene expression and several of these genes also exhibit epigenetic changes. This might contribute to the impaired insulin secretion seen in T2D.