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Modulation of insulin degrading enzyme activity and liver cell proliferation

Olga Pivovarova1, Christian von Loeffelholz, Iryna Ilkavets

  • 1a Department of Clinical Nutrition ; German Institute of Human Nutrition Potsdam-Rehbruecke ; Nuthetal , Germany.

Cell Cycle (Georgetown, Tex.)
|May 7, 2015
PubMed

Insights

Insulin degrading enzyme (IDE) expression decreases in the liver of type 2 diabetes mellitus (T2DM) patients. IDE inhibition in liver cells did not increase proliferation, suggesting caution for IDE inhibitors in T2DM therapy.

Area of Science:

  • Hepatology
  • Endocrinology
  • Molecular Biology

Background:

  • Type 2 diabetes mellitus (T2DM), hyperinsulinemia, and insulin therapy are linked to liver cancer risk.
  • Inhibitors of insulin degrading enzyme (IDE) are a potential T2DM treatment, but may increase liver cell proliferation.

Purpose of the Study:

  • To investigate the effects of IDE inhibition on HepG2 hepatoma cells.
  • To analyze liver-specific IDE expression in T2DM patients.

Main Methods:

  • HepG2 cells were treated with insulin and IDE inhibition via RNA interference (RNAi).
  • Cell transcriptome and proliferation were analyzed.
  • Gene expression profiling of human liver samples (n=22) from T2DM patients using microarrays.

Main Results:

  • IDE knockdown in HepG2 cells altered cell cycle and apoptosis gene expression, reducing proliferation.
  • Liver samples from T2DM patients showed decreased IDE expression.
  • Downregulation of p53-dependent genes (FAS, CCNG2) was observed in T2DM livers, without increased proliferation markers.

Conclusions:

  • Hepatic IDE expression is reduced in T2DM patients, associated with p53 pathway dysregulation.
  • IDE inhibition's effect on hepatic tumorigenesis requires careful evaluation in preclinical studies before T2DM therapeutic use.
Keywords:
CCNG2, Cyclin G2 gene, CDKN1A/P21, Cyclin-dependent kinase inhibitor 1A (p21, Cip1) geneCDKN1B/P27, Cyclin-dependent kinase inhibitor 1B (p27, Kip1) geneFAS, Fas cell surface death receptor geneFBS, Fetal bovine serumIDE, Insulin-degrading enzymeMCM2, Minichromosome maintenance complex component 2 geneMKI67, Marker of proliferation Ki-67 geneNAFLD, Non-alcoholic fatty liver diseaseNAS, Non-alcoholic fatty liver disease scoreOGTT, Oral glucose tolerance testPCNA, Proliferating cell nuclear antigen geneSESN1, Sestrin 1 geneT2DM, Type 2 diabetes mellitus.TP53, Tumor protein p53 geneTP53I3, Tumor protein p53 inducible protein 3 genehepatocellular carcinomainsulin-degrading enzymenon-alcoholic fatty liver diseaseproliferationqRT-PCR, Quantitative real-time PCRtype 2 diabetes mellitus

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