Dyslipidemia and Vascular Dysfunction in Diabetic Pigs Fed an Atherogenic Diet

Dixon, John R.; Stoops, Janelle; Parker, Janet L.; Laughlin, M. Harold; Weisman, Gary A.; Sturek, Michael

doi:10.1161/01.atv.19.12.2981

Cited by 127 publications

(159 citation statements)

References 62 publications

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“…Although statistically significant, this increase was minute compared with the 14-fold increase in LDL ϩ VLDL cholesterol, which comprised Ͼ96% of the total cholesterol in hyperlipemic animals. We have no explanation for the increase in HDL cholesterol observed in fat-fed swine, but it has been previously observed by ourselves and others in both swine (19,20,52) and other diet-induced hyperlipemic animal models (55), and may simply be an effect of the huge increase in total cholesterol. As in humans (31,32), however, diabetic animals tended to have lower HDL cholesterol levels than nondiabetic animals, but differences in actual levels were not statistically significant, in accord with findings in alloxaninduced diabetes in swine (52).…”

Section: Discussionmentioning

confidence: 58%

“…We have no explanation for the increase in HDL cholesterol observed in fat-fed swine, but it has been previously observed by ourselves and others in both swine (19,20,52) and other diet-induced hyperlipemic animal models (55), and may simply be an effect of the huge increase in total cholesterol. As in humans (31,32), however, diabetic animals tended to have lower HDL cholesterol levels than nondiabetic animals, but differences in actual levels were not statistically significant, in accord with findings in alloxaninduced diabetes in swine (52). Perhaps of more relevance to the accelerated atherosclerosis in this model is that the total cholesterol-to-HDL cholesterol ratio, which is generally increased in human diabetic subjects, was increased significantly by diabetes in both normolipemic and hyperlipemic swine (38 and 28%, respectively).…”

Section: Discussionmentioning

confidence: 58%

“…The swine erythrocyte is highly impermeable to glucose (53,54), such that glycated hemoglobin is not a useful indicator of diabetes in this model. Recent studies in alloxan-treated pigs (52), however, demonstrated increased levels of other glycated plasma proteins after only 1 week of diabetes.…”

Section: Discussionmentioning

confidence: 96%

“…Review of the literature has revealed no detailed studies on atherosclerosis in diabetic swine. Although spontaneous diabetes has been reported in Yucatan miniature swine (48 -51), only one recent study (52) in a small number of alloxan-treated Sinclair miniature swine has demonstrated enhanced arterial sudanophilia at prelesion stages. To our knowledge, the current study is the first to describe and quantify diabetes-induced accelerated atherosclerosis in multiple arterial beds over an extended period of time.…”

Section: Discussionmentioning

confidence: 99%

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Diabetes-Induced Accelerated Atherosclerosis in Swine

et al. 2001

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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...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Diabetes-Induced Accelerated Atherosclerosis in Swine

et al. 2001

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“…72,73 Diets in genetically susceptible strains and chemical destruction of islets have been used to create diabetic pigs. Alloxan-treated diabetic pigs have increased atherosclerosis; 74 however, plasma LDL was more than doubled by the diabetes. A later study examined the effect of type 1 diabetes in high-fat diet, STZ-treated pigs.…”

Section: Does Diabetes Increase Atherosclerosis In Animals?mentioning

confidence: 95%

Diabetic Vascular Disease

Goldberg

Dansky

2006

ATVB

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Abstract-It is well known that humans with diabetes have more atherosclerosis and its complications. The causes of this relationship are, however, unclear. Although recent data show that improved glycemic control reduces arterial disease in type 1 diabetes, other studies have shown that subjects with "prediabetes" have more cardiovascular disease before the development of hyperglycemia. Thus, either hyperglycemia and/or lack of insulin actions are toxic to arteries, or metabolic derangements exclusive of hyperglycemia are atherogenic. For Ͼ50 years animal models of diabetes and atherosclerosis have been used to uncover potential mechanisms underlying diabetes associated cardiovascular disease. Surprisingly, diabetes alone increases vascular disease in only a few select animal models. Increased atherosclerosis has been found in several animals and lines of genetically modified mice; however, diabetes often also leads to greater hyperlipidemia. This makes it difficult to separate the toxic effects of insulin lack and/or hyperglycemia from those caused by the lipids. These studies are reviewed, as well as more recent investigations using new methods to create diabetic-atherosclerotic models.

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Large animal models of cardiovascular disease

Tsang

Rashdan

Whitelaw

et al. 2016

Cell Biochemistry & Function

118

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The human cardiovascular system is a complex arrangement of specialized structures with distinct functions. The molecular landscape, including the genome, transcriptome and proteome, is pivotal to the biological complexity of both normal and abnormal mammalian processes. Despite our advancing knowledge and understanding of cardiovascular disease (CVD) through the principal use of rodent models, this continues to be an increasing issue in today's world. For instance, as the ageing population increases, so does the incidence of heart valve dysfunction. This may be because of changes in molecular composition and structure of the extracellular matrix, or from the pathological process of vascular calcification in which bone‐formation related factors cause ectopic mineralization. However, significant differences between mice and men exist in terms of cardiovascular anatomy, physiology and pathology. In contrast, large animal models can show considerably greater similarity to humans. Furthermore, precise and efficient genome editing techniques enable the generation of tailored models for translational research. These novel systems provide a huge potential for large animal models to investigate the regulatory factors and molecular pathways that contribute to CVD in vivo. In turn, this will help bridge the gap between basic science and clinical applications by facilitating the refinement of therapies for cardiovascular disease. 2016 The Authors. Published by John Wiley & Sons Ltd.

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Dyslipidemia and Vascular Dysfunction in Diabetic Pigs Fed an Atherogenic Diet

Cited by 127 publications

References 62 publications

Diabetes-Induced Accelerated Atherosclerosis in Swine

Diabetes-Induced Accelerated Atherosclerosis in Swine

Diabetic Vascular Disease

Large animal models of cardiovascular disease

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