Significant change in insulin production, glucose tolerance and ER stress signaling in transgenic mice coexpressing insulin-siRNA and human IDE.

The dual expression system for the suppression and clearance of insulin has not been previously used to produce transgenic mice for diabetes-related disease. The aim of this study was to produce new transgenic mice coexpressing specific insulin small interfering RNA (siRNA) sequences and the human insulin degrading enzyme (hIDE) gene in order to examine the diabetes-like phenotype. To achieve this, a new lineage of transgenic mice was produced by the microinjection of the dual expression constructs (pH1/siRNAinsulin-CMV/hIDE) into mouse fertilized eggs. The results showed that overexpressing the insulin siRNA and hIDE genes resulted in the induction of the human enzyme, impaired glucose tolerance and lower serum insulin levels compared to the Non-Tg mice. Moreover, the Tg mice aged 20 weeks had a significantly activated ER stress signaling compared to their Non-Tg counterparts, which may be associated with the suppression of insulin production in the pancreas and the degradation of insulin in the liver, respectively. Therefore, insulin-suppressed transgenic mice can be used to examine diabetes as a new diabetes-like phenotype model, which results in a lower level of circulating insulin without the destruction of pancreatic islets.