Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes

Abstract

ObjectiveGene expression alterations, especially in target tissues of insulin, have been associated with type 2 diabetes (T2D). In this study, we examined if genes involved in oxidative phosphorylation (OXPHOS) show differential gene expression and DNA methylation in pancreatic islets from patients with T2D compared with non-diabetic donors.Design and methodsGene expression was analyzed in human pancreatic islets from 55 non-diabetic donors and nine T2D donors using microarray.ResultsWhile the expected number of OXPHOS genes with reduced gene expression is 7.21, we identified 21 downregulated OXPHOS genes in pancreatic islets from patients with T2D using microarray analysis. This gives a ratio of observed over expected OXPHOS genes of 26.37 by aχ2-test withP=2.81×10−7. The microarray data was validated by qRT-PCR for four selected OXPHOS genes:NDUFA5, NDUFA10, COX11, andATP6V1H. All four OXPHOS genes were significantly downregulated in islets from patients with T2D compared with non-diabetic donors using qRT-PCR (P≤0.01). Furthermore, HbAlc levels correlated negatively with gene expression ofNDUFA5, COX11, andATP6V1H(P<0.05). Gene expression ofNDUFA5, NDUFA10, COX11, andATP6V1Hcorrelated positively with glucose-stimulated insulin secretion (P<0.03). Finally, DNA methylation was analyzed upstream of the transcription start forNDUFA5, COX11, andATP6V1H. However, none of the analyzed CpG sites in the three genes showed differences in DNA methylation in islets from donors with T2D compared with non-diabetic donors.ConclusionPancreatic islets from patients with T2D show decreased expression of a set of OXPHOS genes, which may lead to impaired insulin secretion.