Study of DNA methylation in human pancreatic islets

Detta är en avhandling från Epigenetics and Diabetes

Sammanfattning: Today type 2 diabetes is a common disease with a worldwide prevalence of 8.3%. The disease is characterised by hyperglycaemia which is a result of insufficient insulin secretion from the beta-cells in the pancreatic islets as well as an insulin resistance seen in the target tissues. Type 2 diabetes is a multifactorial disease with genetic, epigenetic and environmental background. In study I we investigated the role of sex-specific DNA methylation in pancreatic islets from human organ donors. We found DNA methylation differences between the sexes for the average DNA methylation on the X chromosome, as well as site specific differences on both the X chromosome as well as the autosomes. We could also connect some of these differences to changes in gene expression and insulin secretion. In study II we studied a specific gene, GLP1R, which is involved in the incretin effects seen on the pancreatic beta-cells. Using human pancreatic islets, we found correlations between DNA methylation of a specific site in the GLP1R promoter and gene expression of the same gene as well as with HbA1c and BMI. Furthermore, DNA methylation of the same site was also differentially methylated in FACS sorted human alpha- and beta-cells. In study III we studied the role palmitate on human pancreatic islets. We treated the human islets in control media or media enriched with palmitate for 48 hours. We found a decreased glucose-stimulated insulin secretion in human islets treated with palmitate compared to controls, but no increase in apoptosis. Also we found differences of gene expression between groups as well as DNA methylation differences in genomic regions and specific genes. In Study IV we investigated the role of high glucose on the human pancreatic islets and therefor treated the islets with either control medium or high glucose medium. We found that insulin secretion was perturbed in islets treated with high glucose compared to controls. Furthermore, we found gene expression differences of eight genes, with five of them also having DNA methylation differences. In conclusion we find signs that sex, palmitate and high glucose treatment affect gene expression, DNA methylation and in some cases also beta-cell function in human pancreatic islets. Furthermore we find indications of that DNA methylation of the GLP1R promoter might affect gene expression and might be connected to HbA1c and obesity.

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