Increased atherosclerosis in streptozotocin-induced diabetic mice.

Abstract

Premature and extensive atheroscleroses involving renal, peripheral, and cardiovascular sites remain major complications of diabetes mellitus. Controversy exists as to the contribution of hyperglycemia versus elevated local or systemic concentrations of insulin to atherosclerosis risk. In this report, we developed the first murine model susceptible to both atherosclerosis and diabetes to determine which diabetogenic factors contribute to vascular disease. C57BL/6 and BALB/c mice were treated with multiple low-dose streptozotocin (

The emergence of mouse models of atherosclerosis and their relevance to clinical research

“…Feeding an inhibitor of acyl-CoA (cholesterol acyltransferase; ACAT) along with the Paigen diet decreased VLDL ϩ LDL cholesterol levels and aortic root lesion area [36]. LeBoeuf 's laboratory determined that streptozotocin induced diabetes, although it had no effect on diet-induced atherosclerosis in the susceptible C57BL/6 strain, induced 17-fold larger lesions in the atherosclerosis-resistant BALB/c strain [37]. In addition, this study demonstrated a correlation between plasma glucose and atherosclerosis lesion size in the diabetic BALB/c mice, and the results infer that hyperglycaemia, and not the hyperinsulinaemia associated with type II diabetes, is the primary atherogenic factor associated with diabetes [37].…”

“…LeBoeuf 's laboratory determined that streptozotocin induced diabetes, although it had no effect on diet-induced atherosclerosis in the susceptible C57BL/6 strain, induced 17-fold larger lesions in the atherosclerosis-resistant BALB/c strain [37]. In addition, this study demonstrated a correlation between plasma glucose and atherosclerosis lesion size in the diabetic BALB/c mice, and the results infer that hyperglycaemia, and not the hyperinsulinaemia associated with type II diabetes, is the primary atherogenic factor associated with diabetes [37]. It has also been demonstrated that aortic root lesion area, as well as VLDL ϩ LDL cholesterol levels, increases in female C57BL/6 mice housed five per cage versus those housed individually [38].…”

Molecular and Cellular Mechanisms by Which Diabetes Mellitus Promotes the Development of Atherosclerosis

“…In commonly used rodent strains, hyperglycemia and diabetes alone are not sufficient to promote the development of lesions [24]. Even in strains that can develop vascular lesions, diabetesaccelerated atherosclerosis appears, in many cases, to depend upon hyperlipidemia, either resulting from a high fat diet or a genetic deficiency, as with the ApoE-deficient or LDLR-deficient mouse [24,25]. The general resistance of mice to atherogenesis may result, at least in part, from the observation that wild-type mice, in contrast with humans, have barely detectable lowdensity lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels.…”

“…The general resistance of mice to atherogenesis may result, at least in part, from the observation that wild-type mice, in contrast with humans, have barely detectable lowdensity lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels. The induction of hyperlipidemia, through dietary or genetic manipulation, "humanizes" the lipid profiles of mice by significantly elevating both VLDL and LDL [24][25][26].…”

“…In low-to-moderate doses, STZ is selectively toxic to pancreatic β cells. STZ-induced diabetes accelerates atherosclerosis in ApoE-deficient mice and BALBc mice fed an atherogenic diet [24,25]. An advantage of the alloxan and STZ-induced models of diabetes mellitus is that they permit the examination of the effects of hyperglycemia in the absence of other variables that are often associated with T2D including obesity and hyperinsulinemia.…”