PT  - JOURNAL ARTICLE
AU  - Jiangming Sun
AU  - Ruchi Jain
AU  - Lotta E. Andersson
AU  - Anya Medina
AU  - Petter Storm
AU  - Peter Spégel
AU  - Hindrik Mulder
TI  - Perturbed Mitochondrial Metabolism in Islets from Donors with Type-2 Diabetes
AID  - 10.1101/212548
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 212548
4099  - http://biorxiv.org/content/early/2017/11/01/212548.short
4100  - http://biorxiv.org/content/early/2017/11/01/212548.full
AB  - There is a preponderance for genes involved in ß-cell function among gene variants associated with future risk of type-2 diabetes (T2D). ß-cell function is controlled by metabolism of glucose, yielding signals triggering and amplifying insulin secretion. Perturbed ß-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, α-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 ß-cell dysfunction in T2D.[Supplementary material is available for this article.]