title: Mutation in insulin receptor attenuates oxidative stress and apoptosis in pancreatic beta-cells induced by nutrition excess: reduced insulin signaling and ROS.
abstract: Type 2 diabetes results from the failure of beta-cells to adequately compensate for insulin resistance. Although the reduction of beta-cell mass is because of increased cell death and/or inadequate replication or neogenesis, the mechanism underlying beta-cell mass reduction is not fully understood. Here, we clarify the role of insulin signaling pathway in the beta-cell apoptosis using insulin resistant model mice. Wild-type mice and those carrying a mutation in the insulin receptor (mIR) were fed either regular chow or a high-fat diet for 6 weeks and subsequently investigated for beta-cell apoptosis, endoplasmic reticulum stress, and oxidative stress. Insulin tolerance tests revealed that mIR mice fed a high-fat diet (mIRHF) had higher insulin resistance. Beta-cell apoptosis was increased 2-fold in the wild-type mice fed a high-fat diet (wHF) compared with control mice, whereas beta-cell apoptosis in mIRHF mice did not increase compared with that in mIR mice. The expression of endoplasmic reticulum stress markers in isolated islets did not differ between the groups. Staining of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal in islets of wHF mice significantly increased, but the staining in mIRHF mice was not different from that in control group. Gene expression of the antioxidant enzyme MnSOD was significantly higher in mIRHF mice than those in the other 3 groups. A mutation in the insulin receptor attenuated the oxidative stress and apoptosis in beta-cells even though high caloric nutrient was loaded. Our results suggest that reduced insulin signaling protects beta-cells thorough decline of oxidative stress.
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tachibana
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yokoh
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.|Department of Aging Control Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shirasawa
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yokote
mesh_terms: D000818:Animals; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin