Modulation of insulin degrading enzyme activity and liver cell proliferation

Abstract

Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n = 22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis.

Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

“…Thus, our findings suggested that hyperglycemia may provoke the disturbance of IDE activity in T2DM. Moreover, we found a decrease of IDE mRNA expression in the liver of diabetic subjects (67). Further, decreased hepatic insulin degradation is an early marker of a disturbed insulin metabolism in obesity and T2DM (68,69), and prodiabetic genetic polymorphisms of the IDE gene are associated with reduced insulin clearance (56).…”

“…T2DM is known to be an independent risk factor for hepatocellular carcinoma (76) possibly via chronic hyperinsulinemia. We recently found that RNAi IDE knockdown induces dysregulation of p53 pathway and an increase of proliferation markers in HepG2 hepatoma cells, although the proliferation rate was lower in IDE knockdown cells than in controls (67). Analysis of microarray datasets from liver samples of diabetic subjects revealed a decrease of IDE expression accompanied by downregulation of the p53-dependent genes FAS and CCNG2, but not by upregulation of proliferation markers (67).…”

Insulin-degrading enzyme: is it suitable for diabetes treatment?

“…Both models were accompanied by disturbances in the p53 pathway, which might affect tumorigenesis in the liver. 6 Whether this is a direct effect of IDE or mediated by changes in the proteasome-ubiquitin system is not clear. Certainly the effects of inhibition of IDE have to be carefully investigated -not only in liver, but also in other tissues, as brain and pancreatic islands -in order to make this a suitable future strategy of type 2 diabetes treatment.…”

Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus

“…Likewise, other authors found a decrease of Ide mRNA expression in the liver of diabetic subjects [184].…”

“…Some of these authors report increased IDE levels in plasma and human erythrocytes of T2DM patients, both in insulin-and non-insulin dependent patients [180] and [181]. In contrast, other studies reported low IDE expression in other tissues from diabetic patients, such as adipocytes [182] and liver [184]. There is a single study in the literature that reports IDE levels in pancreatic islets of diabetic patients.…”