The db/db mouse, a model for diabetic dyslipidemia: Molecular characterization and effects of Western diet feeding

Diabetic dyslipidemia is a major factor contributing to the accelerated ath erosclerosis in type 2 diabetes mellitus, Although several mouse models are available, the plasma lipoproteins in response to diet have not been fully characterized in these animals. In this study, we have characterized the p lasma lipoproteins and related apolipoproteins, as well as the vascular lip ases, in diabetes (db/db) mice and their nondiabetic controls (+/?) in the C57BL/KsJ strain. Within 6 weeks of age, db/db mice developed significant o besity, fasting hyperglycemia, and hyperinsulinemia. By FPLC analysis, db/d b mice showed a prominent peak in the low-density lipoprotein (LDL) range t hat was absent in +/? mice, although high-density lipoprotein (HDL) was the predominant species in both groups of animals. Postheparin lipoprotein lip ase (LPL) activity in db/db mice was 28% of the level in +/? mice. Upon fee ding a human-like 0.15% (wt/wt) cholesterol and 21% (wt/wt) fat "Western" d iet, db/db mice developed elevated plasma cholesterol, accompanied by an ex aggerated apolipoprotein E (apoE) response compared with +/? mice. FPLC ana lysis showed that the marked hypercholesterolemic response in db/db mice wa s the result of a massive increase in the LDL region, which overshadowed a moderate increase in HDL. We next isolated lipoproteins by ultracentrifugat ion and characterized them by nondenaturing gradient gel electrophoresis. W ith regular chow, db/db mice had almost exclusively small dense LDL with a peak size at 21.4 nm, as compared with 26.6 nm in nondiabetic controls. On the Western diet, the small dense LDLs persisted but larger particles also appeared in db/db mice, whereas the size distribution in +/? mice was uncha nged by the diet. Our results suggest that db/db mice fed a Western diet ha ve a plasma lipoprotein phenotype that shows some similarities to that in p atients with type 2 diabetes mellitus, and that db/db mice are a useful mod el to study the pathogenesis and treatment of diabetic dyslipidemia. Copyri ght (C) 2000 by W.B. Saunders Company.