title: 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.
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Damilola D
authors: DD
authors: Adingupu
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Suvi E
authors: 0000-0001-5237-0132
authors: SE
authors: Heinonen
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Anne-Christine
authors: AC
authors: Andréasson
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Mikael
authors: 0000-0002-1609-5169
authors: M
authors: Brusberg
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Andrea
authors: A
authors: Ahnmark
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Margareta
authors: 0000-0003-3068-7627
authors: M
authors: Behrendt
authors: The Research Network, Sandwich, UK.
authors: Brendan
authors: 0000-0001-8282-6735
authors: B
authors: Leighton
authors: CVMD iMED, AstraZeneca R&D, Gothenburg, Sweden.
authors: Ann-Cathrine
authors: 0000-0002-6706-9657
authors: AC
authors: Jönsson-Rylander
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D018450:Disease Progression; D005260:Female; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D005941:Glucokinase