Abstract
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.glucokinase+/− (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.
Highlights
The metabolic syndrome consists of a cluster of cardiovascular risk factors, including abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels, and drives the global epidemics of type 2 diabetes (T2D) and cardiovascular disease (CVD)
Plasma pooled per group showed lower aspartate transaminase (AST) and alanine transaminase (ALT) values as markers of hepatocellular damage in GK+/− mice when compared to E3L.GK+/− mouse by cross-breeding dyslipidemic APOE∗3-Leiden (E3L).GK+/− and E3L
Since no additional effects of glucose were observed on hepatic inflammation or fibrosis in the E3L.GK+/− mice, we suggest that hyperlipidemia rather than hyperglycemia is an initiator of hepatic inflammation and fibrosis
Summary
The metabolic syndrome consists of a cluster of cardiovascular risk factors, including abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels, and drives the global epidemics of type 2 diabetes (T2D) and cardiovascular disease (CVD). Diabetes increases the CVD risk about twofold [1,2,3], which is the leading cause of death worldwide, and aggravates nonalcoholic steatohepatitis (NASH) [4] and diabetic nephropathy [5] These comorbidities emphasize the need for antidiabetic treatments that. Most available models are dyslipidemic mice, e.g., ApoE−/− and LDLr−/− mice, with chemically (STZ) or genetically (ob/ob, db/db, and IRS2−/−) induced diabetes [6] These models are widely used in biomedical research and drug development, they do not sufficiently reflect human disease. 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. 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
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