LEW.1WR1 Rats have increased insulin levels and liver lipid lipolytic gene expression during their type 1 diabetes susceptibility window.

Abstract

LEW.1WR1(1WR1) rats have increased type 1 diabetes (T1D) onset with the administration of polyinosinic‐polycytidylic acid (PIC). The susceptibility window of inducible T1D in the 1WR1 rat occurs between 21–35 days of life. The susceptibility of this model is related to FAT10 overexpression, a ubiquitin‐like protein that plays an unclear role in disease induction and the regulation of lipid metabolism. We hypothesized that these rodents have altered liver lipid metabolism due to increased FAT 10 gene expression in their livers and increased circulating insulin levels which can lead to decreased liver insulin sensitivity and increased beta‐cell sensitivity to inflammation. The objective of this study was to compare the insulitis status and liver gene expression in both control and treated 1WR1 rats during disease induction with a T1D‐resistant strain of rat, the LEW/SSNHsd.Using immunohistochemistry we observed higher T cell infiltration in the 1WR1 treated rats compared to the control strain, the LEW/SsNHsd(SsNHsd) PIC‐treated rat. By correlating plasma glucose levels measured by glucometer with this finding we confirmed that the 1WR1 rats were not undergoing significant insulitis at the time point we selected. We also observed that the rats have significantly fewer total islets than the SsNHsd rats but remained normoglycemic. Interestingly the 1WR1 treated rat had significantly increased insulin levels compared to the SsNHsd rats, as previous studies showed a 3 fold increase in the 1WR1 rat compared to Wistar Furth rats in a similar study(unpublished data). Both groups of the 1WR1 rats also had increased liver FAT10 gene expression compared to the SsNHsd. We measured liver lipid lipolytic gene expression to assess the metabolic status of the livers at this time point. We observed 1WR1 rats have increased expression of genes related to lipid catabolism like SREBP‐1 (Sterol Regulatory Element‐binding Protein‐1), ATGL (Adipose triglyceride lipase), DGAT1(diacylglycerol acyltransferase‐1), DGAT2(diacylglycerol acyltransferase‐2) and lower expression of glucose metabolism‐related genes like GLUT2(Glucose transporter 2), suggesting that the 1WR1 rats may have had a liver sensitivity response to the hyperinsulinemia. In conclusion, 1WR1 rats have reduced insulin sensitivity in the context of increased inflammation due to PIC injection which led to beta‐cell sensitivity and eventual T‐cell mediated destruction.Support or Funding InformationDepartment of Chemistry, UAHDepartment of Biology, UAHCollege of Science, UAHOffice of Provost, UAH