Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.
James DooleyLei TianSusann SchonefeldtViviane Delghingaro-AugustoJosselyn E Garcia-PerezEmanuela PasciutoDaniele Di MarinoEdward J CarrNikolay OskolkovValeriya LyssenkoDean FranckaertVasiliki LagouLut OverberghJonathan VandenbusscheJoke AllemeerschGenevieve Chabot-RoyJane E DahlstromD Ross LaybuttNikolai PetrovskyLuis SochaKris GevaertAnton M JettenDiether LambrechtsMichelle A LintermanChris C GoodnowChristopher J NolanSylvie LesageSusan M SchlennerAdrian ListonPublished in: Nature genetics (2016)
Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.
Keyphrases
- type diabetes
- single cell
- cardiovascular disease
- glycemic control
- cell therapy
- induced apoptosis
- multiple sclerosis
- genome wide
- metabolic syndrome
- endothelial cells
- stem cells
- cell death
- gene expression
- insulin resistance
- copy number
- dna methylation
- mesenchymal stem cells
- endoplasmic reticulum stress
- dna repair
- wild type