RT Journal Article SR Electronic T1 Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice JF Diabetes JO Diabetes FD American Diabetes Association SP db200881 DO 10.2337/db20-0881 A1 Omori, Kazuno A1 Nakamura, Akinobu A1 Miyoshi, Hideaki A1 Yamauchi, Yuki A1 Kawata, Shinichiro A1 Takahashi, Kiyohiko A1 Kitao, Naoyuki A1 Nomoto, Hiroshi A1 Kameda, Hiraku A1 Cho, Kyu Yong A1 Terauchi, Yasuo A1 Atsumi, Tatsuya YR 2021 UL http://diabetes.diabetesjournals.org/content/early/2021/01/27/db20-0881.abstract AB 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.