Reduced Insulin Signaling and Endoplasmic Reticulum Stress Act Synergistically to Deteriorate Pancreatic β Cell Function
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概要
- 論文の詳細を見る
The total pancreatic β cell mass is reduced in individuals with type 2 diabetes. Weanalyzed the islets of leptin receptor-deficient (Lepr-/-) mice, a model animal for type 2diabetes with obesity. The plasma insulin levels in Lepr-/- mice peaked at~approximately 7 weeks, an age at which the animals manifest normoglycemia tomoderate hyperglycemia. Consistent with this, the β cell mass was enlarged ascompared with Lepr+/- mice, and it decreased thereafter. Thus, we focused on the isletsof Lepr-/- mice at 7 weeks to elucidate the mechanism underlying β cell failure.Endoplasmic reticulum (ER) stress was enhanced in β cells of Lepr-/- mice at 7 weeks, asindicated by the increase in c-Jun and eIF2α phosphorylation. Lepr-/- mice alsoexhibited a reduction in insulin signaling in β cells at 7 weeks, as indicated by thedecrease in Akt phosphorylation. These results indicate that both augmented ER stressand reduced insulin signaling occur before the onset of frank diabetes. Next, to examinethe mutual effect of ER stress and insulin signaling in β cells in vitro, we used MIN6insulinoma cells. Tunicamycin induced ER stress as well as inhibited insulin signaling.Conversely, the PI-3 kinase inhibitor, LY294002, enhanced ER stress. Furthermore, thereduction in insulin signaling by LY294002 facilitated the induction of ER stress withtunicamycin. Taken together, we concluded that both ER stress and reduced insulinsignaling might synergistically affect pancreatic β cell dysfunction.
- 神戸大学の論文
著者
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Kasuga Masato
Department Of Hospital Pharmacy School Of Medicine Kobe University
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Kasuga Masato
Department Of Clinical Molecular Medicine Division Of Diabetes Digestive And Kidney Diseases
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KIDO Yoshiaki
Department of Nuclear Engineering,Faculty of Engineering,Kyoto University
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Matsuda Tomokazu
Department Of Internal Medicine Takasago Municipal Hospital
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Matsuda Tomokazu
Department Of Internal Medicine Division Of Diabetes Metabolism And Endocrinology Kobe University Gr
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Kasuga Masato
Department Of Internal Medicine Division Of Diabetes Metabolism And Endocrinology Kobe University Gr
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Kido Yoshiaki
Department Of Internal Medicine Division Of Diabetes Metabolism And Endocrinology Kobe University Gr
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Uchida Tohru
Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe Universit
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Uchida Tohru
Department Of Internal Medicine Division Of Diabetes Metabolism And Endocrinology Kobe University Gr
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