The Overexpression of Insulin-siRNA and Insulin Degrading Enzyme Decreases Insulin Levels In vitro and In vivo

Type 2 or noninsulin-dependent diabetes mellitus accounts for over 90% of cases and is characterized by a triad of resistance to insulin action on glucose uptake in peripheral tissues, impaired insulin action to inhibit hepatic glucose production, and dysregulated insulin secretion. To determine whether a transgene-based small interfering RNA (siRNA) for insulin and an overexpression of human insulin degrading enzyme (hIDE) decrease the insulin level in vitro and in vivo or not, several siRNA sequences and hIDE gene for insulin were overexpressed in the insulinoma cells and mouse via tail vein. The siRNAs for insulin suppression were very effective at the regions of 88-99 bp and 109-131 bp in rat insulin sequence. Insulin suppression by the specific siRNA sequences and hIDE significantly induced endoplasmic reticulumn (ER) stress and decreased insulin receptor a expression in insulinoma cells. The insulin level in plasma significantly decreased by overexpressions of the siRNAs and hIDE gene in mouse, which may be caused by the degradation of insulin due to overexpression of hIDE protein in mouse liver. These results suggest that this plasmid for the suppression of insulin secretion by the specific siRNAs and the insulin degradation by an overexpression of hIDE protein may be useful on the development of animal model for Type 2 diabetes.