Gene Expression in LEW.1WR1 Rats Indicate Insulin Resistance in Muscle and Liver Tissue

Abstract

FAT10 is a ubiquitin‐like protein and type 1 diabetes (T1D) susceptibility gene that may play a role in age‐related inflammation, adiposity, cancer, and kidney disease. The young T1D susceptible, LEW.1WR1 rat overexpresses FAT10 and has higher fasting concentrations of blood insulin. It is unclear how the overexpression of FAT10 directly affects insulin sensitivity. It is also unclear if the initial insulin sensitivity of this animal model plays a role in disease susceptibility. We measured the relative expression of lipid and glucose metabolism genes in skeletal muscle and liver tissue in LEW.1WR1 and LEW/ssNHsd rats to determine if 12‐week old LEW.1WR1 rats were insulin resistant. We also tested the gene expression in pancreatic islets to determine if there were changes in endocrine pancreas cell health and hormone production. The results indicate that gene expression increased in the islets for glucagon, insulin, and PLIN5 (Perilipin‐5), and cyclin D expression decreased in LEW.1WR1 rats, suggesting reduced compensation and a potentially lipotoxic environment for beta cells. The increase in glucagon and insulin also supports peripheral insulin resistance. In liver tissue, UBD (Ubiquitin‐D), a gene suspected to regulate beta‐oxidation, was increased. INSIG (Insulin‐induced gene 1) and GLUT2 (Glucose transporter 2) gene expression decreased, indicating decreased expression of insulin‐regulated gene and glucose transporters, respectively. In muscle tissues, ATGL (Adipose triglyceride lipase), GAPDH (Glyceraldehyde‐3‐Phosphate Dehydrogenase), and PNPLA2 (Patatin Like Phospholipase Domain Containing 2) gene expression decreased, indicating a reduced ability to burn fat as energy and glucose intolerance in muscle tissue. These results, in tandem with previous work, suggest that fat storage in organs may account for the difference in weight previously observed between LEW.1WR1 and LEW/ssNHsd rats, and that LEW.1WR1 rats were developing insulin resistance which further suggests these rats are a novel animal model for pre‐diabetes.Support or Funding InformationThe authors would like to thank the UAH Office of the Vice President for Research and Economic Development, The Alabama Space Grant Consortium, ALSAMP, Adriel D. Johnson Sr. Fellowship, College of Science, Department of Chemistry, Department of Biology, Honors College, and Office of the Provost for the financial support for the resources, supplies, and student salaries.