title: Metformin Protects Kidney Cells From Insulin-Mediated Genotoxicity In Vitro and in Male Zucker Diabetic Fatty Rats.
abstract: Hyperinsulinemia is thought to enhance cancer risk. A possible mechanism is induction of oxidative stress and DNA damage by insulin, Here, the effect of a combination of metformin with insulin was investigated in vitro and in vivo. The rationales for this were the reported antioxidative properties of metformin and the aim to gain further insights into the mechanisms responsible for protecting the genome from insulin-mediated oxidative stress and damage. The comet assay, a micronucleus frequency test, and a mammalian gene mutation assay were used to evaluate the DNA damage produced by insulin alone or in combination with metformin. For analysis of antioxidant activity, oxidative stress, and mitochondrial disturbances, the cell-free ferric reducing antioxidant power assay, the superoxide-sensitive dye dihydroethidium, and the mitochondrial membrane potential-sensitive dye 5,5',6,6'tetrachloro-1,1',3,3'-tetraethylbenzimidazol-carbocyanine iodide were applied. Accumulation of p53 and pAKT were analyzed. As an in vivo model, hyperinsulinemic Zucker diabetic fatty rats, additionally exposed to insulin during a hyperinsulinemic-euglycemic clamp, were treated with metformin. In the rat kidney samples, dihydroethidium staining, p53 and pAKT analysis, and quantification of the oxidized DNA base 8-oxo-7,8-dihydro-2'-deoxyguanosine were performed. Metformin did not show intrinsic antioxidant activity in the cell-free assay, but protected cultured cells from insulin-mediated oxidative stress, DNA damage, and mutation. Treatment of the rats with metformin protected their kidneys from oxidative stress and genomic damage induced by hyperinsulinemia. Metformin may protect patients from genomic damage induced by elevated insulin levels. This may support efforts to reduce the elevated cancer risk that is associated with hyperinsulinemia.
authors.affiliation: Institute of Pharmacology and Toxicology (E.M.O., R.G.O., H.S.), University of Würzburg, D-97078 Würzburg, Germany; Department of Analytical Chemistry (E.M.O.), Faculty of Pharmacy, University of El-Minia, 61519 Minia, Egypt; and Department of Nuclear Medicine (P.-A.A.-L., M.C.K.), University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: Eman Maher
authors.initials: EM
authors.lastname: Othman
authors.affiliation: Institute of Pharmacology and Toxicology (E.M.O., R.G.O., H.S.), University of Würzburg, D-97078 Würzburg, Germany; Department of Analytical Chemistry (E.M.O.), Faculty of Pharmacy, University of El-Minia, 61519 Minia, Egypt; and Department of Nuclear Medicine (P.-A.A.-L., M.C.K.), University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: R G
authors.initials: RG
authors.lastname: Oli
authors.affiliation: Institute of Pharmacology and Toxicology (E.M.O., R.G.O., H.S.), University of Würzburg, D-97078 Würzburg, Germany; Department of Analytical Chemistry (E.M.O.), Faculty of Pharmacy, University of El-Minia, 61519 Minia, Egypt; and Department of Nuclear Medicine (P.-A.A.-L., M.C.K.), University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: Paula-Anahi
authors.initials: PA
authors.lastname: Arias-Loza
authors.affiliation: Institute of Pharmacology and Toxicology (E.M.O., R.G.O., H.S.), University of Würzburg, D-97078 Würzburg, Germany; Department of Analytical Chemistry (E.M.O.), Faculty of Pharmacy, University of El-Minia, 61519 Minia, Egypt; and Department of Nuclear Medicine (P.-A.A.-L., M.C.K.), University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kreissl
authors.affiliation: Institute of Pharmacology and Toxicology (E.M.O., R.G.O., H.S.), University of Würzburg, D-97078 Würzburg, Germany; Department of Analytical Chemistry (E.M.O.), Faculty of Pharmacy, University of El-Minia, 61519 Minia, Egypt; and Department of Nuclear Medicine (P.-A.A.-L., M.C.K.), University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D019610:Cytoprotection; D004249:DNA Damage / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology*; D006946:Hyperinsulinism / Q000139:chemically induced* / Q000150:complications; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007004:Hypoglycemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D008687:Metformin