The APOE*3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis

Background. There is a lack of predictive preclinical animal models combining atherosclerosis and type 2 diabetes. APOE*3-Leiden (E3L) mice are a well-established model for diet-induced hyperlipidemia and atherosclerosis, and glucokinase(+/-) (GK(+/-)) mice are a translatable disease model for glucose control in type 2 diabetes. The respective mice respond similarly to lipid-lowering and antidiabetic drugs as humans. The objective of this study was to evaluate/characterize the APOE*3-Leiden.glucoldnase" (E3L.GK(+/-)) mouse as a novel disease model to study the metabolic syndrome and diabetic complications. Methods. Female (E3L.GK(+/-)) E3L, and GK(+/-) mice were fed fat- and cholesterol-containing diets for 37 weeks, and plasma parameters were measured throughout. Development of diabetic macro- and microvascular complications was evaluated. Results. Cholesterol and triglyceride levels were significantly elevated in E3L and (E3L.GK(+/-)) mice compared to GK(+/-) mice, whereas fasting glucose was significantly increased in (E3L.GK(+/-))and GK(+/-) mice compared to E3L. Atherosclerotic lesion size was increased 2.2-fold in(E3L.GK(+/-)) mice as compared to E3L (p = 0.037), which was predicted by glucose exposure (R-2 = 0.636, p = 0.001). E3L and (E3L.GK(+/-)) mice developed NASH with severe inflammation and fibrosis which, however, was not altered by introduction of the defective GK phenotype, whereas mild kidney pathology with tubular vacuolization was present in all three phenotypes. Conclusions. We conclude that the (E3L.GK(+/-)) mouse is a promising novel diet-inducible disease model for investigation of the etiology and evaluation of drug treatment on diabetic atherosclerosis.