DOCUMENT
1/1
Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice
figure
posted on 2021-02-18, 21:50 authored 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 AtsumiEfficacy 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.