Hepatic Transcriptome Analysis Revealing the Molecular Pathogenesis of Type 2 Diabetes Mellitus in Zucker Diabetic Fatty Rats

Abstract

Around 9% of the adult population in the world (463 million) suffer from diabetes mellitus. Most of them (~90%) belong to type 2 diabetes mellitus (T2DM), which is a common chronic metabolic disorder, and the number of cases has been reported to increase each year. Zucker diabetic fatty (ZDF) rat provides a successful animal model to study the pathogenesis of T2DM. Although previous hepatic transcriptome studies revealed some novel genes associated with the occurrence and development of T2DM, there still lacks the comprehensive transcriptomic analysis for the liver tissues of ZDF rats. We performed comparative transcriptome analyses between the liver tissues of ZDF rats and healthy ZCL rats and also evaluated several clinical indices. We could identify 214 and 104 differentially expressed genes (DEGs) and lncRNAs in ZDF rats, respectively. Pathway and biofunction analyses showed a synergistic effect between mRNAs and lncRNAs. By comprehensively analyzing transcriptomic data and clinical indices, we detected some typical features of T2DM in ZDF rats, such as upregulated metabolism (significant increased lipid absorption/transport/utilization, gluconeogenesis, and protein hydrolysis), increased inflammation, liver injury and increased endoplasmic reticulum (ER) stress. In addition, of the 214 DEGs, 114 were known and 100 were putative T2DM-related genes, most of which have been associated with substance metabolism (particularly degradation), inflammation, liver injury and ER stress biofunctions. Our study provides an important reference and improves understanding of molecular pathogenesis of obesity-associated T2DM. Our data can also be used to identify potential diagnostic markers and therapeutic targets, which should strengthen the prevention and treatment of T2DM.

Keywords: ER stress; Zucker diabetic fatty (ZDF) rats; hepatic transcriptome; inflammation; liver injury; molecular pathogenesis; substance metabolism; type 2 diabetes mellitus (T2DM).