Effect of Streptozotocin-Induced Hyperglycemia on Lipid Profiles, Formation of Advanced Glycation Endproducts in Lesions, and Extent of Atherosclerosis in LDL Receptor-Deficient Mice

Abstract

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.

Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

“…Glucose concentrations measured after a 16-h fast were higher in Bhmt ϩ/ϩ (158 Ϯ 6 mg/dl) than in Bhmt Ϫ/Ϫ mice (119 Ϯ 10 mg/dl, p Ͻ 0.05). Glucose values were at the high end of what have been reported for C57Bl mice (130 -218 mg/dl for a 4-h fast (25)(26)(27)(28)(29) and 90 -120 mg/dl for a 12-16 h fast (27,30)). …”

RAGE Axis

“…35 These findings were in contradistinction to the work of Reavan et al These investigators found that induction of diabetes by streptozotocin in LDL receptorϪ/Ϫ mice fed a high-fat diet over an extended time course did not result in acceleration of atherosclerosis. 36 We posit that the differences between these 2 study outcomes may be ascribed, at least in part, to the premise that at the aortic root, the degree of atherosclerosis that may be achieved is finite. Thus, especially over long time courses in Western diet-fed mice, differences between diabetic and nondiabetic groups may become less apparent as atherosclerosis in the nondiabetic animals continues to progress.…”

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

“…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.…”

“…When fed such diets, these mice develop extensive atherosclerosis in the vicinity of the aortic valve (as seen in other atherosclerosissusceptible strains of mice), as well as in the arch, thoracic, and abdominal regions of the aorta. 7,[23][24][25][26] These aortic plaques show many morphological similarities to human atherosclerotic lesions and consist of both fatty streaks and more advanced lesions. 7,25 Given the close phylogenetic relationship between the mouse and the rat, we presumed that a fructose-rich diet would also lead to IR in mice.…”

“…7,[23][24][25][26] These aortic plaques show many morphological similarities to human atherosclerotic lesions and consist of both fatty streaks and more advanced lesions. 7,25 Given the close phylogenetic relationship between the mouse and the rat, we presumed that a fructose-rich diet would also lead to IR in mice. Furthermore, we presumed that a fructose-rich diet would result in an increased production of VLDL in LDLR Ϫ/Ϫ mice (as in rats) and, because of the reduced clearance of lipoproteins caused by the lack of LDL receptors, to elevated plasma cholesterol levels, which could be matched in control LDLR Ϫ/Ϫ mice by feeding them a standard Western diet.…”