Genetic and epigenetic influence on oxidative phosphorylation, islet function and type 2 diabetes in humans

The prevalence of type 2 diabetes (T2D) is increasing worldwide. T2D is a heterogeneous disease caused by a complex interplay between multiple genetic, epigenetic and non-genetic factors. The disease is characterised by impaired insulin secretion from pancreatic β-cells and insulin resistance in peripheral tissues. Mitochondrial ATP production by oxidative phosphorylation (OXPHOS) is known to play a critical regulatory role in glucose stimulated insulin secretion (GSIS). The overall aim of this thesis was to explore the influence of genetic and epigenetic variation on OXPHOS, islet function and T2D in humans. In study I, we identified a single nucleotide polymorphism (SNP) in TFB1M, a nuclear-encoded factor involved in the translational control in mitochondria, that is associated with decreased insulin secretion in response to glucose, increased future risk of T2D, and reduced expression of TFB1M in human pancreatic islets. In mice with a heterozygous deficiency of Tfb1m and in clonal β-cells where Tfb1m had been silenced, we found that reduced levels of TFB1M caused impaired OXPHOS and, consequently, reduced insulin secretion. This study concludes that deficiency in TFB1M contributes to the pathogenesis of T2D by causing impaired insulin secretion. In study II, we showed that SNPs located adjacent to OXPHOS genes are nominally associated with decreased GSIS. Therefore, we cannot rule out the possibility that SNPs in or near genes involved in OXPHOS may influence β-cell function. In study III, we demonstrated that a set of OXPHOS genes is down-regulated in pancreatic islets from patients with T2D compared to donors not diagnosed with diabetes. Islet expression of multiple OXPHOS genes correlated positively with GSIS. This result suggests that decreased expression of OXPHOS genes in pancreatic islets may contribute to T2D by impaired GSIS. In study IV, we performed a genome-wide methylation quantitative trait locus (mQTL) analysis to assess the effects of SNPs on DNA methylation in human pancreatic islets. Our results demonstrate that DNA methylation in pancreatic islets is under the control of genetic variability, suggesting the importance of integrating genetic and epigenetic mechanisms when studying the underlying biological effects on complex human diseases, such as T2D. Taken together, genetic and epigenetic influence on pancreatic islet function and mitochondrial OXPHOS may be involved in the pathogenesis of T2D by affecting insulin secretion