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

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posted on 18.02.2021, 21:50 by Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Yuki Yamauchi, Shinichiro Kawata, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related with the excess glucose signalling by glucokinase activation towards 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 db/db mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance 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, higher 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 signalling 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 could, paradoxically, be a potential strategy for the treatment of type 2 diabetes.

Funding

Akiyama Life Science Foundation Japan Agency for Medical Research and Development (AMED) x Japan Association for Diabetes Education and Care x Ministry of Education, Culture, Sports, Science and Technology (MEXT) x 19K08992 26860683 MSD x Suhara Memorial Foundation Suzuken Memorial Foundation Takeda Science Foundation

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