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Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes
Author(s) -
Baker D J,
Atkinson A M,
Wilkinson G P,
Coope G J,
Charles A D,
Leighton B
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12498
Subject(s) - glucokinase , metformin , sitagliptin , endocrinology , medicine , type 2 diabetes , diabetes mellitus , glipizide , insulin , pharmacology , chemistry
Background and Purpose The global heterozygous glucokinase ( GK ) knockout ( gk wt/del ) male mouse, fed on a high‐fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes ( T2D ). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose‐lowering potential of novel glucokinase activators (GKAs) in this model. Experimental Approach We measured the ability of insulin, metformin, glipizide, exendin‐4 and sitagliptin, after acute or repeat dose administration, to lower free‐feeding glucose levels in gk wt/del mice. Further, we measured the ability of novel GKAs , GKA 23, GKA 71 and AZD 6370 to control glucose either alone or in combination with some standard agents. Key Results A single dose of insulin (1 unit·kg −1 ), metformin (150, 300 mg·kg −1 ), glipizide (0.1, 0.3 mg·kg −1 ), exendin‐4 (2, 20 μg·kg −1 ) and GKAs reduced free‐feeding glucose levels. Sitagliptin (10 mg·kg −1 ), metformin (300 mg·kg −1 ) and AZD 6370 (30, 400 mg·kg −1 ) reduced glucose excursions on repeat dosing. At a supra‐therapeutic dose (400 mg·kg −1 ), AZD 6370 also lowered basal levels of glucose without inducing hypoglycaemia. Conclusion and Implications Standard glucose‐lowering therapeutic agents demonstrated significant acute glucose lowering in male gk wt/del mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D . Novel GKAs also lowered glucose in this mouse model.