Académie royale de Médecine de Belgique

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Vidéo et résumé de Miriam Cnop


                               

Novel human induced pluripotent stem cell-β cell models to study disease mechanisms in diabetes

 by Miriam CNOP (ULB), membre associée.          

The heterogeneity in clinical presentation of type 2 diabetes points to a complex pathophysiology, with diverse routes leading to β cell failure. Genetic variants and environmental stresses, such as high fat diets, play an important role. Our work has focused on the role of saturated free fatty acids in β cell failure. We identified endoplasmic reticulum (ER) stress as a cellular response contributing to free fatty acid-induced β cell apoptosis. Signaling in the PERK branch of the ER stress response in particular leads to lipotoxic β cell demise. Mitochondrial dysfunction also contributes to β cell failure in type 2 diabetes.

Monogenic forms of diabetes can be used a simpler models of organelle dysfunction to dissect disease mechanisms. We have therefore turned to human “knockouts”, i.e. patients with monogenic diabetes caused by loss-of-function mutations in genes with a role in ER stress signaling or mitochondrial function. Five monogenic forms of diabetes are caused by mutations in the PERK branch, providing strong human genetic evidence for the importance of PERK signaling in maintaining β cell integrity. Dysregulated eIF2∝ phosphorylation and mRNA translation in these human diseases leads to β cell demise. We have also studied diabetes pathogenesis in Friedreich ataxia, a monogenic mitochondrial disease, and identified a central role for β cell dysfunction and apoptosis in the loss of glucose tolerance in these patients. The differentiation of these patients’ induced pluripotent stem cells into β cells provides an exciting species- and disease-relevant model to study molecular mechanisms of β cell failure and test β cell protective therapies.