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 c...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2019/9727952 |
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| author | Marianne G. Pouwer Suvi E. Heinonen Margareta Behrendt Anne-Christine Andréasson Arianne van Koppen Aswin L. Menke Elsbet J. Pieterman Anita M. van den Hoek J. Wouter Jukema Brendan Leighton Ann-Cathrine Jönsson-Rylander Hans M. G. Princen |
| author_facet | Marianne G. Pouwer Suvi E. Heinonen Margareta Behrendt Anne-Christine Andréasson Arianne van Koppen Aswin L. Menke Elsbet J. Pieterman Anita M. van den Hoek J. Wouter Jukema Brendan Leighton Ann-Cathrine Jönsson-Rylander Hans M. G. Princen |
| author_sort | Marianne G. Pouwer |
| collection | DOAJ |
| description | 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 (R2=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. |
| format | Article |
| id | doaj-art-fcb568a4dba0410dbde997fd34268ac7 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-fcb568a4dba0410dbde997fd34268ac72025-02-03T07:24:05ZengWileyJournal of Diabetes Research2314-67452314-67532019-01-01201910.1155/2019/97279529727952The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic AtherosclerosisMarianne G. Pouwer0Suvi E. Heinonen1Margareta Behrendt2Anne-Christine Andréasson3Arianne van Koppen4Aswin L. Menke5Elsbet J. Pieterman6Anita M. van den Hoek7J. Wouter Jukema8Brendan Leighton9Ann-Cathrine Jönsson-Rylander10Hans M. G. Princen11Metabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, NetherlandsCardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, SwedenCardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, SwedenCardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, SwedenMetabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, NetherlandsTNO-Triskelion, Zeist, NetherlandsMetabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, NetherlandsMetabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, NetherlandsCardiology, Leiden University Medical Center, Leiden, NetherlandsCardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, SwedenCardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, SwedenMetabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, NetherlandsBackground. 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 (R2=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.http://dx.doi.org/10.1155/2019/9727952 |
| spellingShingle | Marianne G. Pouwer Suvi E. Heinonen Margareta Behrendt Anne-Christine Andréasson Arianne van Koppen Aswin L. Menke Elsbet J. Pieterman Anita M. van den Hoek J. Wouter Jukema Brendan Leighton Ann-Cathrine Jönsson-Rylander Hans M. G. Princen The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis Journal of Diabetes Research |
| title | The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis |
| title_full | The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis |
| title_fullStr | The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis |
| title_full_unstemmed | The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis |
| title_short | The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis |
| title_sort | apoe∗3 leiden heterozygous glucokinase knockout mouse as novel translational disease model for type 2 diabetes dyslipidemia and diabetic atherosclerosis |
| url | http://dx.doi.org/10.1155/2019/9727952 |
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