Effects of insulin sensitizers on plaque vulnerability associated with elevated lipid content in atheroma in ApoE-knockout mice.
Acute coronary syndromes are generally precipitated by rupture of lipid-laden, relatively acellular, vulnerable atherosclerotic plaques with thin fibrous caps. We investigated whether a high-fat diet alters insulin sensitivity and whether insulin sensitizers (troglitazone and rosiglitazone) alter the composition of otherwise lipidladen atherosclerotic plaques in mice deficient in apolipoprotein E (ApoE). ApoE-knockout mice were fed a high-fat (n=30) or standard chow (n=10) diet for two weeks. Thereafter, those fed the high-fat diet were treated with troglitazone (n=10), rosiglitazone (n=10) or no drug (n=10) for 16 weeks beginning at 8 weeks of age. Carbohydrate metabolism was assessed with intraperitoneal glucose tolerance tests and insulin tolerance tests. Plaque composition was characterised with confocal laser scanning microscopy. The high-fat diet induced insulin resistance in the absence of weight gain. Compared with control animals on the high-fat diet, animals given troglitazone (400 mg/kg/day) or rosiglitazone (4 mg/kg/day) had significantly less area under the curve (AUC) for insulin ( p<0.05) and glucose disposal ( p<0.05). Despite significant increases in insulin sensitivity with drug treatment, no change in HDL-cholesterol and triglyceride levels, nor reduction in atheroma size or lipid content was noted. Thus, improvement in insulin resistance induced by a high-fat diet in this animal model of vasculopathy did not alter plaque composition.
Cefalu
W T
WT
University of Vermont College of Medicine, UHC Campus, Arnold 3433, One South Prospect Street, 05401, Burlington, VT, USA. CefaluWT@pbrc.edu
Wang
Z Q
ZQ
Schneider
D J
DJ
Absher
P M
PM
Baldor
L C
LC
Taatjes
D J
DJ
Sobel
B E
BE
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood* / Q000172:deficiency*; D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016893:Carotid Stenosis / Q000473:pathology / Q000503:physiopathology; D004036:Diet, Atherogenic; D004198:Disease Susceptibility; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal
D001057:Apolipoproteins E; D007004:Hypoglycemic Agents; D008055:Lipids