Details

Autor(en) / Beteiligte

• Othman, Eman Maher
• Hintzsche, Henning
• Stopper, Helga

Titel

Signaling steps in the induction of genomic damage by insulin in colon and kidney cells

Ist Teil von

• Free radical biology & medicine, 2014-03, Vol.68, p.247-257

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Diabetes mellitus (DM), a disease with almost 350 million people affected worldwide, will be the seventh leading cause of death by 2030. Diabetic patients develop various types of complications, among them an increased rate of malignancies. Studies reported the strong correlation between DM and several cancer types, of which colon and kidney cancers are the most common. Hyperinsulinemia, the high insulin blood level characteristic of early diabetes type 2, was identified as a risk factor for cancer development. In previous studies, we showed that an elevated insulin level can induce oxidative stress, resulting in DNA damage in colon cells in vitro and in kidney cells in vitro and in vivo. In the present study, we elucidate the signaling pathway of insulin-mediated genotoxicity, which is effective through oxidative stress induction in colon and kidney. The signaling mechanism is starting by phosphorylation of the insulin and insulin-like growth factor-1 receptors, followed by activation of phosphatidylinositide 3-kinase (PI3K), which in turn activates AKT. Subsequently, mitochondria and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) isoforms (Nox1 and Nox4 in colon and kidney, respectively) are activated for reactive oxygen species (ROS) production, and the resulting excess ROS can attack the DNA, causing DNA oxidation. We conclude that hyperinsulinemia represents an important risk factor for cancer initiation or progression as well as a target for cancer prevention in diabetic patients. •Diabetic patients suffer from hyperinsulinemia and have higher cancer risk than normal individuals.•Insulin mediates genotoxicity in colon and kidney cells.•Insulin stimulates reactive oxygen species production.•The mitochondria and NADPH oxidases are included in insulin genotoxicity.