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 APPROACHWe 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 ), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia.
CONCLUSION AND IMPLICATIONSStandard 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.