Diabetic atherosclerosis mouse models

Abstract

Coronary heart disease (CHD) due to atherosclerosis is the leading cause of death in the USA, and accelerated CHD has emerged as a leading cause of morbidity and mortality in diabetic patients in the USA and worldwide. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and exploring therapeutic options. Due to its unique advantages over other animal models, the mouse is the most used model for studying the mechanism of diabetes-accelerated atherosclerosis and exploring effective therapeutic approaches. In the past decade, several diabetic atherosclerosis mouse models have been established. Currently, however, there is no ideal animal model for diabetic atherosclerosis. To determine the characteristics of the models that more closely resemble human diabetic atherosclerosis disease, this review focuses on the common diabetic atherosclerosis mouse models with respect to the following issues: (1) whether the mice retain diabetic condition; (2) whether the diabetes accelerates atherosclerosis or increases atherogenic inflammation; (3) whether these factors respond to medical interventions. The discussion is aimed at identifying different diabetic mouse models and their features, in order to heighten awareness of the appropriate models that may provide useful tools for studying the mechanism of diabetes-accelerated atherosclerosis and evaluating therapeutic options.

Introduction

Coronary heart disease (CHD) due to atherosclerosis is the leading cause of mortality in the United States and results in about 500,000 deaths each year [1], [2]. The incidence/prevalence of, and mortality from, all forms of cardiovascular disease are 2–8-fold higher in persons with diabetes than in those without diabetes [3], [4]. In fact, accelerated CHD in diabetic patients has emerged as a leading cause of morbidity and mortality both in the USA and worldwide [5]. This has prompted the National Cholesterol Education Program (NCEP) in the USA to upgrade diabetes mellitus (DM) to be equivalent to CHD in the Adult Treatment Panel III (ATP III) [2]. In 2001, the American Heart Association defined five general groups of factors involved in diabetic atherosclerosis (metabolic factors, oxidation/glucoxidation, endothelial dysfunction, inflammation, and a prothrombotic state) [3], [6]. However, the mechanism of diabetes-accelerated atherosclerosis is still not well understood.

Diabetes mellitus (DM) is a chronic metabolic disorder affecting about 17 million people in the USA [4], [7]; there are 170 million cases worldwide, and this figure is expected to more than double by 2030 [8]. In patients with DM, the worst complication and the most common cause of death is CHD. DM is conventionally divided into type 1 (insulin-dependent diabetes mellitus) and type 2 (non-insulin-dependent diabetes mellitus). Although both types have the same characteristic (hyperglycemia), their prevalence, pathogenesis, mechanism, plasma lipid profile, clinical treatment, complications, and outcomes are quite different. For example, type 1 DM is due to insulin deficiency, is less often associated with dyslipidemia, and is treated by supplying insulin. On the other hand, type 2 DM, which accounts for 95% of DM, is due to insulin resistance; its phenotype includes dyslipidemia characterized by elevated small dense LDL levels, lowered HDL levels, and elevated triglyceride levels [6], [8], [9]; the treatment of type 2 DM is aimed at correcting the patient's insulin resistance. Therefore, it is important to choose an appropriate diabetic animal model for each type of diabetes when doing diabetic atherosclerosis research.

Despite the fact that there are limitations associated with mouse diabetic atherosclerosis models, currently, the mouse model is still the most widely used model to study diabetes and atherosclerosis. The limitations of these mouse models include two major parts. The first one is that mouse models cannot completely mimic human disease, so the extrapolation of relationships seen with human disease to mice is not straightforward. The second one is that most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia [10], which makes it difficult to distinguish the effects of diabetes from the effects of worsening hyperlipidemia on the development of atherosclerosis. However, the leading position of mouse diabetic atherosclerosis model has not been replaced by other animal models, because the mouse model has unique advantages over other animal models. These advantages include: the small size of the animal, short generation time, the ease of induction of diabetes and/or atherosclerosis by diet, drug treatment or a genetic approach, and cost effectiveness [11]. Hence, in the past decade, several diabetic atherosclerosis mouse models have been established and used to study diabetic atherosclerosis (Table 1, Table 2).

None of the currently used models is a perfect diabetic atherosclerosis mouse model. Thus, this review focuses on the common diabetic atherosclerosis mouse models to identify the features of each model that closely resemble human diabetic atherosclerosis disease. A better diabetic atherosclerosis mouse model should have three characteristics: (1) the diabetic condition should persist; (2) the diabetes should accelerate atherosclerosis or increase atherogenic inflammation; (3) the effects should not be refractory to medical intervention. We review the models based on these three points, and catalog them as types 1 and 2 diabetic atherosclerosis mouse models (Table 1, Table 2).