Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice
- 18 February 2021
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 70 (4), 917-931
- https://doi.org/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 β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-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 β-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 β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.Keywords
Funding Information
- The Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Agency for Medical Research and Development
- Japan Association for Diabetes Education and Care
- MSD Life Science Foundation
- Suzuken Memorial Foundation
- Akiyama Life Science Foundation
- Takeda Science Foundation
- Suhara Memorial Foundation
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