Loss of pancreatic beta cell functions and identity during type 2 diabetes: uncovering the role of epitranscriptome. – epiRNA-T2D

Type 2 Diabetes (T2D) is characterized by high blood glucose levels and develops due to inadequate pancreatic ß-cell mass and function (i.e. insulin secretion) in the face of peripheral insulin resistance. ß-cell dysfunction is thought to have a major role in the pathogenesis of T2D. The restoration of ß-cell mass, identity and function has therefore become a field of intensive research seeking for the next generation of anti-diabetic drugs.
Tremendous efforts and illuminating investigations focus on deciphering epigenetic regulations –the subtle and reversible chemical modifications on DNA or proteins– that control ß-cell function. Yet, the analysis and understanding of modifications on RNA in T2D physiopathology at the ß-cell level are currently lagging behind. In the current proposal, we aim to establish the concept that posttranscriptional modifications of RNAs, named epitranscriptome, may contribute to pancreatic ß-cell dysfunctions and defective insulin secretion during metabolic stress, thus favoring the susceptibility to T2D. Our research program aims to go beyond the current state-of-the-art by decoding the epitranscriptome and its underlying mechanisms within the ß cells. We propose to develop an innovative framework to uncover the physiological and pathophysiological roles of these epitranscriptomic modifications of RNA in the regulation of cellular responses during T2D development. This hypothesis will be tested combining unbiased next-generation sequencing technology, mouse models, CRISPR/Cas9, mouse and human cohort studies to dissect the RNA-modification-mediated regulated processes involved in the control of metabolic homeostasis. Thereby, we hope to identify novel targets, open new research fields and emerging concepts for the prevention, diagnosis and treatment of T2D. We believe that deciphering the epitranscriptomic code of ß cells will identify a new layer of information that controls gene expression, protein synthesis and tissue function.