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Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing beta-Cell Mass in db/db Mice

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Title: Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing beta-Cell Mass in db/db Mice
Authors: Omori, Kazuno Browse this author
Nakamura, Akinobu Browse this author →KAKEN DB
Miyoshi, Hideaki Browse this author
Yamauchi, Yuki Browse this author
Kawata, Shinichiro Browse this author
Takahashi, Kiyohiko Browse this author
Kitao, Naoyuki Browse this author
Nomoto, Hiroshi Browse this author
Kameda, Hiraku Browse this author
Cho, Kyu Yong Browse this author
Terauchi, Yasuo Browse this author
Atsumi, Tatsuya Browse this author
Issue Date: Apr-2021
Publisher: American Diabetes Association
Journal Title: Diabetes
Volume: 70
Issue: 4
Start Page: 917
End Page: 931
Publisher DOI: 10.2337/db20-0881
Abstract: Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward beta-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as beta-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in beta-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of beta-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve beta-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in beta-cells by inhibiting glucokinase could prevent beta-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving beta-cell mass. Therefore, glucokinase inactivation in beta-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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