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

Abstract

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...

Rosiglitazone Reduces the Accelerated Neointima Formation After Arterial Injury in a Mouse Injury Model of Type 2 Diabetes

“…However, there was no increase in spontaneous atherosclerosis in the aorta compared with LDLR Ϫ/Ϫ mice on a FD. 35 In addition, compared with the development of insulin resistance, as determined by insulin release profiles in our apoE Ϫ/Ϫ mice fed a FD, the LDLR Ϫ/Ϫ mice did not develop insulin resistance while on a FD. 35 Previous studies in the LDLR Ϫ/Ϫ mice have shown a reduction in lesion formation in male mice treated with thiazolidinediones but not female mice, as we report in our experiments.…”

“…35 In addition, compared with the development of insulin resistance, as determined by insulin release profiles in our apoE Ϫ/Ϫ mice fed a FD, the LDLR Ϫ/Ϫ mice did not develop insulin resistance while on a FD. 35 Previous studies in the LDLR Ϫ/Ϫ mice have shown a reduction in lesion formation in male mice treated with thiazolidinediones but not female mice, as we report in our experiments. 25,26 It is important to note that these studies evaluated spontaneous atherosclerosis in the aortic cusp and aorta in contrast to the model of arterial injury and carotid lesion formation in our experiments.…”

Diabetic Vascular Disease

“…91 Insulin resistance by itself did not alter lesion area. 92 In other studies diabetic LDL receptor knockout mice developed more lesions associated with a marked increase in plasma cholesterol. 58 A recent paper described experiments in which early lesions in chow fed mice were increased with viral destruction of the pancreatic islets.…”

“…When normalized for plasma cholesterol levels, in some studies fructose ingestion is associated with greater lesion development. 92 …”

Renal Accumulation of Biglycan and Lipid Retention Accelerates Diabetic Nephropathy

“…Female mice were used because male mice can develop a type 2 diabetes-like phenotype on high-fat/high-cholesterol diets. 23 Mice were housed in a specific pathogen-free facility with 12-hour light/dark cycles and had free access to food and water. These studies were approved by the Animal Care and Use Committees of the University of Kentucky and the Lexington Veterans Affairs Medical Center.…”