Modulation of insulin degrading enzyme activity: A link between T2DM and liver cancer?

Diabetes mellitus Type 2, insulin therapy and hyperinsulinemia are risk factors of liver cancer in recently published prospective studies. Insulin degrading enzyme (IDE) is a major enzyme responsible for insulin degradation in the liver. Recently, the use of a novel IDE inhibitor was proposed as a new therapeutic strategy to treat type 2 diabetes. Here we hypothesized that IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration and characterized effects of IDE knockdown on the transcriptome and proliferation rate of HepG2 hepatoma cells. We found that IDE knockdown dysregulated expression of genes involved in the cell cycle and apoptosis. In details, the expression of p53-dependent pro-apoptotic genes, FAS and CCNG2, was decreased, whereas the expression of TP53I3 and SESN1 increased in IDE knockdown cells compared to controls. Furthermore, proliferation markers MKI67, MCM2 and PCNA were significantly up-regulated. Nevertheless, the proliferation rate was lower in IDE knockdown cells compared to controls. We conclude that the using of IDE inhibitors for diabetic treatment should be carefully tested regarding its potential effect on hepatic tumorogenesis in animal studies