Perturbed Mitochondrial Metabolism in Islets from Donors with Type-2 Diabetes

There is a preponderance for genes involved in {beta}-cell function among gene variants associated with future risk of type-2 diabetes (T2D). {beta}-cell function is controlled by metabolism of glucose, yielding signals triggering and amplifying insulin secretion. Perturbed {beta}-cell metabolism is a likely, albeit not proven, cause of T2D. We profiled metabolites in islets from T2D and non-diabetic donors, and found altered levels of mitochondrial metabolites in T2D. Analysis of genes encoding proteins localized to mitochondria (MitoCarta) by RNA-seq in an extended sample of islets revealed genes whose expression was associated with glycaemia- and/or BMI. Expression of two of these, -methylacyl-CoA racemase (AMACR) and methylmalonyl-CoA mutase (MUT), was influenced by genetic variation (cis-eQTL). Silencing of AMACR and MUT in insulin-secreting cells reduced hormone secretion by 40-50%. In conclusion, by linking the metabolome to the transcriptome, we showed that perturbed mitochondrial metabolism is a feature of {beta}-cell dysfunction in T2D.\n\n[Supplementary material is available for this article.]