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

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, GKA23, GKA71 and AZD6370 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 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.

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes.

BACKGROUND AND PURPOSE: Pharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D. EXPERIMENTAL APPROACH: Two validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk(wt/del) mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined. KEY RESULTS: Treatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk(wt/del) mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose-stimulated insulin secretion. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans.