Integrated-omics Study Of Deteriorating Pancreatic Islets In Type 2 Diabetes

Progressive reduction in pancreatic ?-cell mass and function comprise the core of the pathogenesis mechanism of type 2 diabetes(T2D).Multiple factors have been found to contribute to pancreatic ?-cell failure,including endoplasmic reticulum stress,oxidative stress,activation of inflammatory pathways as well as alternative splicing(AS).The process of deteriorating pancreatic islets,in which a complex network of molecular events is involved,is not yet fully characterized.By utilizing the state-of-art RNA-Seq and proteomic technologies,we carried out a large-scale time series analysis of transcriptome and proteome in pancreatic islets of Goto-Kakizaki(GK)rats,one of the best-characterized animal models of spontaneous T2D,from 4 to 24 weeks of age.Our omics data set outlines the dynamics of the molecular network during the deterioration of GK islets as two stages:The early stage(4-6 weeks)is characterized by anaerobic glycolysis,inflammation priming,and compensation for insulin synthesis,and the late stage(8-24 weeks)is characterized by inflammation amplification and compensation failure of pancreatic ? cell function.Further time course analysis allowed us to reveal 5,551 differentially expressed genes(DEGs),a large portion of which have not been reported before.Our comprehensive and temporal transcriptome and proteome data offer a valuable resource for the diabetes research community and for quantitative biology.In addition,we also identify a novel function of DEAD-box helicase 1(DDX1)in the regulation of mRNA AS in pancreatic ? cell.By performing integrated data analysis of RNA-Seq and CLIP-Seq,we found hundreds of alternative splicing genes(ASGs)that are targeted by DDX1.These DDX1-targeted AS Gs are mainly associated with calcium ion binding,high voltage-gated calcium channel,and transmembrane transporter.In addition,calcium signaling and insulin secretion are impaired in the pancreatic ? cells after DDX1 knockdown.Our data reveal an important role for DDX1 in the regulation of gene AS and insulin secretion in pancreatic? cells.