TY - JOUR
T1 - Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet
AU - Merat, Shiva
AU - Casanada, Florencia
AU - Sutphin, Mary
AU - Palinski, Wulf
AU - Reaven, Peter D.
PY - 1999/5
Y1 - 1999/5
N2 - The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR(-/-)) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR(-/-) mice; and (3) hypercholesterolemic LDLR(-/-) mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR(-/-) mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; n = 16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (n = 18), or regular chow (n=7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849±268 versus 964±234 mg/dL) and much higher than in the chow-fed group (249±21 mg/dL). Final body weights in the Western diet group were higher (39±6.2 g) than in the fructose- (27.8±2.7 g) or chow-fed (26.7±3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187±16 versus 159±12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8±2.9% versus 7.8±2.5% of aortic surface; P<0.01). These results suggest that (1) fructose-enriched diets do not induce IR in LDLR(-/-) mice; (2) the Western diets commonly used in LDLR(-/-) mice may not only induce atherosclerosis, but also IR, potentially complicating the interpretation of results; and (3) IR and hyperinsulinemia do not enhance atherosclerosis in LDLR(-/-) mice, at least under conditions of very high plasma cholesterol levels. The fact that various levels of hypercholesterolemia can be induced in LDLR(-/-) mice by fat-enriched diets and that such diets induce IR and hyperinsulinemia suggest that LDLR(-/-) mice may be used as models to elucidate the effect of IR on atherosclerosis, eg, by feeding them Western diets with or without insulin-sensitizing agents.
AB - The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR(-/-)) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR(-/-) mice; and (3) hypercholesterolemic LDLR(-/-) mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR(-/-) mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; n = 16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (n = 18), or regular chow (n=7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849±268 versus 964±234 mg/dL) and much higher than in the chow-fed group (249±21 mg/dL). Final body weights in the Western diet group were higher (39±6.2 g) than in the fructose- (27.8±2.7 g) or chow-fed (26.7±3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187±16 versus 159±12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8±2.9% versus 7.8±2.5% of aortic surface; P<0.01). These results suggest that (1) fructose-enriched diets do not induce IR in LDLR(-/-) mice; (2) the Western diets commonly used in LDLR(-/-) mice may not only induce atherosclerosis, but also IR, potentially complicating the interpretation of results; and (3) IR and hyperinsulinemia do not enhance atherosclerosis in LDLR(-/-) mice, at least under conditions of very high plasma cholesterol levels. The fact that various levels of hypercholesterolemia can be induced in LDLR(-/-) mice by fat-enriched diets and that such diets induce IR and hyperinsulinemia suggest that LDLR(-/-) mice may be used as models to elucidate the effect of IR on atherosclerosis, eg, by feeding them Western diets with or without insulin-sensitizing agents.
KW - Arteriosclerosis
KW - Diabetes
KW - Fructose
KW - Hypercholesterolemia
KW - Lipoproteins
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UR - http://www.scopus.com/inward/citedby.url?scp=0032936073&partnerID=8YFLogxK
U2 - 10.1161/01.ATV.19.5.1223
DO - 10.1161/01.ATV.19.5.1223
M3 - Article
C2 - 10323773
AN - SCOPUS:0032936073
SN - 1079-5642
VL - 19
SP - 1223
EP - 1230
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -