Increased atherosclerotic lesion calcification in a novel mouse model combining insulin resistance, hyperglycemia, and hypercholesterolemia.

Abstract

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor-deficient mice synthetizing only apolipoprotein B100 (LDLR(-/-) ApoB(100/100)). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR(-/-)ApoB(100/100) mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR(-/-)ApoB(100/100) controls. In addition, old IGF-II/LDLR(-/-)ApoB(100/100) mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR(-/-)ApoB(100/100) mice did not differ from LDLR(-/-)ApoB(100/100) controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.

• Authors: Suvi E Heinonen, Pia Leppänen, Ivana Kholová, Henri Lumivuori, Sanna-Kaisa Häkkinen, Fatima Bosch, Markku Laakso, Seppo Ylä-Herttuala
• Journal: Circulation research (Circ Res) Vol. 101 Issue 10 Pg. 1058-67 (Nov 09 2007) ISSN: 1524-4571 [Electronic] United States
• PMID: 17872464 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins B
• Blood Glucose
• Lipids
• Osteoprotegerin
• Receptors, LDL
• Tnfrsf11b protein, mouse
• Insulin-Like Growth Factor II

Topics

• Animals
• Apolipoproteins B (genetics)
• Atherosclerosis (complications, pathology, physiopathology)
• Blood Glucose
• Calcinosis (complications, pathology, physiopathology)
• Diabetes Mellitus, Type 2 (complications, pathology, physiopathology)
• Diabetic Angiopathies (complications, pathology, physiopathology)
• Disease Models, Animal
• Hypercholesterolemia (complications, pathology, physiopathology)
• Hyperglycemia (complications, pathology, physiopathology)
• Insulin Resistance
• Insulin-Like Growth Factor II (genetics)
• Lipids (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Osteoprotegerin (blood)
• Receptors, LDL (genetics)