Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice
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 hyp...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2016/8630961 |
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| author | Damilola D. Adingupu Suvi E. Heinonen Anne-Christine Andréasson Mikael Brusberg Andrea Ahnmark Margareta Behrendt Brendan Leighton Ann-Cathrine Jönsson-Rylander |
| author_facet | Damilola D. Adingupu Suvi E. Heinonen Anne-Christine Andréasson Mikael Brusberg Andrea Ahnmark Margareta Behrendt Brendan Leighton Ann-Cathrine Jönsson-Rylander |
| author_sort | Damilola D. Adingupu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ecc3d17e5ed04a3f99edd95ddbcc466d |
| institution | DOAJ |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-ecc3d17e5ed04a3f99edd95ddbcc466d2025-08-20T03:21:23ZengWileyJournal of Diabetes Research2314-67452314-67532016-01-01201610.1155/2016/86309618630961Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout MiceDamilola D. Adingupu0Suvi E. Heinonen1Anne-Christine Andréasson2Mikael Brusberg3Andrea Ahnmark4Margareta Behrendt5Brendan Leighton6Ann-Cathrine Jönsson-Rylander7CVMD iMED, AstraZeneca R&D, Gothenburg, SwedenCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenThe Research Network, Sandwich, UKCVMD iMED, AstraZeneca R&D, Gothenburg, SwedenAim. 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.http://dx.doi.org/10.1155/2016/8630961 |
| spellingShingle | Damilola D. Adingupu Suvi E. Heinonen Anne-Christine Andréasson Mikael Brusberg Andrea Ahnmark Margareta Behrendt Brendan Leighton Ann-Cathrine Jönsson-Rylander Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice Journal of Diabetes Research |
| title | Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice |
| title_full | Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice |
| title_fullStr | Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice |
| title_full_unstemmed | Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice |
| title_short | Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice |
| title_sort | hyperglycemia induced by glucokinase deficiency accelerates atherosclerosis development and impairs lesion regression in combined heterozygous glucokinase and the apolipoprotein e knockout mice |
| url | http://dx.doi.org/10.1155/2016/8630961 |
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