Abstract-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 Ϫ/Ϫ ) 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 Ϫ/Ϫ mice; and (3) hypercholesterolemic LDLR Ϫ/Ϫ mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR Ϫ/Ϫ mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; nϭ16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (nϭ18), or regular chow (nϭ7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849Ϯ268 versus 964Ϯ234 mg/dL) and much higher than in the chow-fed group (249Ϯ21 mg/dL). Final body weights in the Western diet group were higher (39Ϯ6.2 g) than in the fructose-(27.8Ϯ2.7 g) or chow-fed (26.7Ϯ3.8 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 (187Ϯ16 versus 159Ϯ12 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 (11.8Ϯ2.9% versus 7.8Ϯ2.5% of aortic surface; PϽ0.01). These results suggest that (1) Key Words: arteriosclerosis Ⅲ diabetes Ⅲ fructose Ⅲ hypercholesterolemia Ⅲ lipoproteins I ndividuals with underlying insulin resistance (IR) and resulting impaired glucose tolerance (IGT) and noninsulin-dependent diabetes mellitus (NIDDM) have an increased prevalence of atherosclerosis and increased rates of coronary heart disease (CHD), 1-5 but the mechanisms responsible are poorly understood. Hyperglycemia has been hypothesized to enhance atherosclerosis in NIDDM, but the specific contribution of hyperglycemia has been difficult to demonstrate in either population studies or animal models. [5][6][7][8] Moreover, hyperglycemia per se is unlikely to play a role in the development of atherosclerosis in individuals with IGT who usually demonstrate only modest postprandial hyperglycemia. Insulin resistance is frequently associated with a number of metabolic abnormalities such as obesity, hypertriglyceridemia, low HDL, and hypertension. These risk factors explain some, but not all, of the increased risk for CHD. 9,10 Thus, additional factors associated with IR are likely to contribute to the accelerated development of atherosclerosis. Hyperinsulinemia is frequently present in both IGT and NIDDM, and several lines of evidence suggest that hyperinsulinemia itself may be proatherogenic. 11,12 For example, insulin has been shown to increase smooth muscle cell proliferation in vitro 11,13 and to enhance accumulation of cholesterol ester in aortas of rats. 14 Although several mechani...

Investigations into the mechanisms by which diabetes accelerates atherosclerosis have been hampered by the lack of suitable animal models. We hypothesized that streptozotocin-treated LDL receptor-deficient mice would be a good model of diabetic atherosclerosis because streptozotocin causes diabetes in the parent C57BL/6 strain and because in these mice diet-induced hypercholesterolemia leads to the formation of advanced atherosclerotic lesions throughout the aorta. Diabetes was induced in 18 mice by intraperitoneal injection of streptozotocin. Low-dose insulin was given subcutaneously to prevent excessive mortality and extreme elevations in triglyceride levels. The control group was subjected to sham injections. Both groups were fed a diet containing .075% cholesterol for six months. Average blood glucose was higher in the diabetic group than in the control group (257 +/- 67 mg/dL versus 111 +/- 7 mg/dL, P < 0.05). Although plasma cholesterol was similar (966 +/- 399 versus 1002 +/- 180 mg/dL) in both groups, VLDL cholesterol was higher whereas LDL cholesterol was lower in the diabetic group. Immunocytochemical analysis demonstrated significantly more advanced glycation end-product (AGE) epitopes in the artery wall of the diabetic group, whereas staining for oxidation-specific epitopes was similar in both groups. Sera of diabetic mice also contained significantly more IgG autoantibodies that bound to several AGE epitopes than did sera from control mice. Despite the presence of hyperglycemia, diabetic dyslipidemia, and enhanced AGE formation in the diabetic mice, both groups had a similar extent of atherosclerosis (diabetic, 17.3 +/- 5.2; control, 16.5 +/- 6.6% of the aortic surface). These data suggest that, at least under conditions of marked hypercholesterolemia; hyperglycemia and enhanced AGE formation do not contribute significantly to atherogenesis in LDL-/- mice.

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