Diabetes-Induced Accelerated Atherosclerosis in Swine

Abstract

Patients with diabetes are at higher risk for atherosclerotic disease than nondiabetic individuals with other comparable risk factors. Studies examining mechanisms underlying diabetes-accelerated atherosclerosis have been limited by the lack of suitable humanoid animal models. In this study, diabetes was superimposed on a well-characterized swine model of atherosclerosis by injection of the ␤-cell cytotoxin streptozotocin (STZ), resulting in a >80% reduction in ␤-cells and an increase in plasma glucose to diabetic levels. Animals were maintained without exogenous insulin for up to 48 weeks. Plasma glucose and cholesterol levels and lesion extent and severity were quantified in swine with diabetes and hyperlipemia alone and in combination compared with controls. Diabetes had no effect on plasma cholesterol levels, P atients with diabetes are at two-to sixfold greater risk of developing atherosclerosis than nondiabetic individuals (1,2), and the most common cause of death in adult diabetic patients is coronary heart disease (3). This excess risk occurs in both type 1 and type 2 diabetes (3). In contrast to nondiabetic subjects, heart disease in diabetic subjects appears earlier in life, affects women almost as often as men, and is more often fatal (3). As many as 80% of all type 2 diabetic patients will die of atherosclerotic macrovascular disease (4), and adult diabetic patients are more susceptible to developing other atherosclerotic risk factors, including hypertension and dyslipidemias (3). Furthermore, data on the efficacy of insulin control of diabetes in ameliorating atherosclerotic disease are inconsistent. Although improvement of glycemic control may reduce the risk of heart disease in type 1 diabetic patients (3), insulin-treated type 2 diabetic patients continue to have increased risk of cardiovascular events (3).The mechanisms underlying the increased risk and greater acceleration and severity of atherosclerotic disease in diabetes remain an enigma due, at least in part, to the lack of suitable humanoid animal models (5,6). In this study, we chose to induce diabetes in an atherosclerotic swine model, which we have extensively characterized over the last two decades (7-15). Swine has proven to be an excellent model for cardiovascular studies, in that the development, morphology, and function of the normal cardiovascular system in swine closely resembles that of humans (16). Swine are also, like humans, omnivores, develop spontaneous atherosclerosis with increased age (17), and have lipoprotein profiles and metabolism similar to humans (7,18 -20). When fed cholesterol-and lipidcontaining diets, they develop humanoid atherosclerosis in most arterial beds in time periods inversely proportional to cholesterol level (7)(8)(9)(10)(11)(12)(13)(14)21). Therefore, by use of streptozotocin (STZ) as a diabetes-inducing agent that we superimposed on the atherosclerotic swine model, we set out to determine the following: 1) whether diabetes could be reproducibly produced and maintained over prolonged time periods in...

Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model

“…Chronic streptozotocin-induced diabetes was produced and maintained in pigs for periods up to 48 weeks [12]. Based on quantitative immunohistochemistry, this resulted in a ninefold loss of pancreatic beta cells in pigs injected with STZ compared with normal pigs (221 86 vs 23 4 beta cells/standardized field) which was maintained throughout this period.…”

“…Urine samples were obtained by bladder puncture before pigs were killed 20 weeks after the initiation of the HL diet. Plasma glucose and lipid measurements were carried out as described previously [12]. Arterial samples were obtained when the pigs were killed from exactly the same site in each animal, rinsed in sterile PBS, and rapidly frozen in liquid nitrogen.…”

“…We earlier established a diet-induced model of atherosclerosis in pigs [11]. In this study, we established a pig model of diabetes-induced accelerated atherosclerosis which shares several features with the human disease [12].…”

“…In this study, we established a pig model of diabetes-induced accelerated atherosclerosis which shares several features with the human disease [12]. This model reflects the conditions in human Type II (non-insulin-dependent) diabetes mellitus, particularly increased triglycerides and vascular-wall calcification.…”

Diabetic Vascular Disease

“…A later study examined the effect of type 1 diabetes in high-fat diet, STZ-treated pigs. 75 Although the induction of diabetes resulted in an increase in plasma triglyceride with no change in LDL cholesterol in the high-fat diet fed pigs, there was worsening of the extent and severity of atherosclerosis in the diabetic compared with the nondiabetic pigs. In both of these studies, the effects of diabetes cannot be discerned because increased lipoprotein levels alone should increase atherosclerosis.…”