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.

A Transcriptomic Response to Lactiplantibacillus plantarum-KCC48 against High-Fat Diet-Induced Fatty Liver Diseases in Mice

“…The gene DMBT1 harbors homozygous deletions and/or lacks expression in malignant human brain tumors, and it was named deleted in malignant brain tumors 1 (Dmbt1) [ 62 ]. Expression of DMBT1 was associated with inflammation response and liver injury [ 63 ]. The DEGs of CTSE and DMBT1 were significantly increased in response to HFD-fed animals, which confirmed that HFD might induce hepatic inflammation and dyslipidemia in mice liver by increasing the mRNA CTSE and DMBT1.…”

Recent advances of long non-coding RNAs in control of hepatic gluconeogenesis

“…Similarly, hepatocytes also have a unique lncRNA expression profile, which changes during liver development and regulates liver maturation (14). RNA-seq revealed 104 differentially expressed lncRNAs in the liver of T2D rats and bioinformatics analysis suggest these lncRNAs may correlate with the pathogenesis of T2D by affecting lipid metabolism, gluconeogenesis, inflammation, and/or endoplasmic reticulum stress (15). Moreover, metformin treatment induced a number of differentially expressed lncRNAs in the liver of mice, implying lncRNAs are involved in hepatic gluconeogenesis since the promising inhibitory effect of metformin on gluconeogenesis (16).…”

Effects of salvianolic acid A on intestinal microbiota and lipid metabolism disorders in Zucker diabetic fatty rats

“…Reducing blood glucose and improving IR are imperative for clinical T2DM treatment [ 56 , 65 ]. To explore T2DM pathogenesis, male Zucker diabetic fatty (ZDF) rats are extensively used as they can aptly simulate the obesity-related T2DM occurrence and progression [ 53 ]. Hence, we selected ZDF rats as study subjects to investigate the mechanism of DM and provide a reference for treatment.…”