Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice

Abstract

Aim. Models combining diabetes and atherosclerosis are important in evaluating the cardiovascular (CV) effects and safety of antidiabetes drugs in the development of treatments targeting CV complications. Our aim was to evaluate if crossing the heterozygous glucokinase knockout mouse (GK+/−) and hyperlipidemic mouse deficient in apolipoprotein E (ApoE−/−) will generate a disease model exhibiting a diabetic and macrovascular phenotype. Methods. The effects of defective glucokinase on the glucose metabolism and on the progression and regression of atherosclerosis on high-fat diets were studied in both genders of GK+/−ApoE−/− and ApoE−/− mice. Coronary vascular function of the female GK+/−ApoE−/− and ApoE−/− mice was also investigated. Results. GK+/−ApoE−/− mice show a stable hyperglycemia which was increased on Western diet. In oral glucose tolerance test, GK+/−ApoE−/− mice showed significant glucose intolerance and impaired glucose-stimulated insulin secretion. Plasma lipids were comparable with ApoE−/− mice; nevertheless the GK+/−ApoE−/− mice showed slightly increased atherosclerosis development. Conclusions. The GK+/−ApoE−/− mice showed a stable and reproducible hyperglycemia, accelerated atherosclerotic lesion progression, and no lesion regression after lipid lowering. This novel model provides a promising tool for drug discovery, enabling the evaluation of compound effects against both diabetic and cardiovascular endpoints simultaneously in one animal model.

Hyperglycemia does not affect tissue repair responses in shear stress-induced atherosclerotic plaques in ApoE−/− mice

“…In line with these findings, Adingupu et al . reported that impaired glucokinase function in ApoE−/− mice on a western diet did not result in accelerated atherosclerotic plaque progression 35 .…”

“…1 ), we used ApoE−/− GK+/− mice with ApoE−/− mice as controls. The impaired function of the glucokinase enzyme in both the pancreas and in the liver results in hyperglycemia and insulin resistance 35 . We analyzed the effects of hyperglycemia on atherosclerotic plaque size and no differences were found in either the carotid artery or in the aortic root for the ApoE−/− GK+/− and the ApoE−/− mice (Fig.…”

“…To rule out the influence of abnormal lipid levels on atherosclerotic lesion progression we used the heterozygous glucokinase knockout apolipoprotein E deficient mouse model that has a consistent diabetic profile. Unlike many other diabetic mouse models these mice have a balanced hyperglycemic profile regardless of the age, and most importantly the effect of a diabetes-induced increase in lipid levels is absent which makes it an appropriate model 35 . To confirm this phenotype we measured the total plasma cholesterol and triglyceride levels and indeed, no difference between the ApoE−/− GK+/− and ApoE−/− mice could be found (Fig.…”

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

“…Previously, the GK +/− ApoE −/− mouse model has been developed as a model combining hyperlipidemia and hyperglycemia, which had impaired glucose tolerance and a minimal increase of atherosclerosis relative to ApoE −/− mice [ 47 ]. A disadvantage of this model is the ApoE −/− background.…”

Animal models of diabetes-associated vascular diseases: An update on available models and experimental analysis

“…Lastly, another note-worthy genetic model of T2D-induced atherosclerosis is the heterozygous glucokinase (GK) knockout mouse on the ApoE -/background. GK is the rate-limiting enzyme of glucose-stimulated insulin secretion, thus is it not surprising that GK +/-/ApoE -/mice on a western diet show significant glucose intolerance and impaired glucose-stimulated insulin secretion, a phenomenon that was consistent over time [55]. Despite plasma lipid levels being comparable to the ApoE -/mouse, GK +/-/ApoE -/mice have significantly accelerated and highly developed atherosclerotic lesions, strongly suggesting that lesions are driven by hyperglycemia and insulin resistance [55].…”