2024-03-29T05:25:03Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/813652022-11-17T02:08:08Zhdl_2115_20040hdl_2115_121Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing beta-Cell Mass in db/db MiceOmori, KazunoNakamura, AkinobuMiyoshi, HideakiYamauchi, YukiKawata, ShinichiroTakahashi, KiyohikoKitao, NaoyukiNomoto, HiroshiKameda, HirakuCho, Kyu YongTerauchi, YasuoAtsumi, Tatsuya490Efficacy 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.American Diabetes AssociationJournal Articlehttp://hdl.handle.net/2115/813650012-1797Diabetes7049179312021-04enginfo:doi/10.2337/db20-0881none