Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes.

background and purposeThe 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, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. KEY

resultsA 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 AZD6370 (30, 400 mg·kg(-1)) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg(-1)), AZD6370 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.