Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies

Abstract

Individuals with type 2 diabetes mellitus have increased cardiovascular disease risk compared with those without diabetes. Treatment of the residual risk, other than blood pressure and LDL-cholesterol control, remains important as the rate of diabetes increases worldwide. The accelerated atherosclerosis and cardiovascular disease in diabetes is likely to be multifactorial and therefore several therapeutic approaches can be considered. Results of mechanistic studies done in vitro and in vivo--animals and people--can provide important insights with the potential to improve clinical management decisions and outcomes. In this Review, we focus on three areas in which pathophysiological considerations could be particularly informative--ie, the roles of hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL-cholesterol concentrations), and inflammation (including that in adipose tissue) in the acceleration of vascular injury.

Figure 1. Potential ways in which glucose and advanced glycation end-products (AGE-proteins) can affect atherogenesis in diabetes

An early event in atherogenesis is adhesion of circulating monocytes to arterial endothelium. They enter the artery wall along a chemotactic gradient. Once inside the artery wall, monocytes can be activated and differentiate into macrophages. Atherogenic lipoproteins cross the endothelial barrier where they can be trapped by vascular proteoglycans and other matrix molecules such as collagen. Once retained by the matrix they can undergo modification by glycoxidation and other processes, which render the lipoproteins more toxic to vascular cells. They also can be taken up by macrophages, resulting in the formation of foam cells. Later, smooth muscle cell migrate from the media to the arterial intima. Glucose (*) and AGEs () have been shown to affect various steps in these pathways as shown.

Figure 2. Diabetic dyslipidemia and the vessel wall

Insulin resistance and relative insulin deficiency in T2DM leads to abnormal lipoprotein particle number, size and composition. These lipoprotein changes impact gene expression and lipid flux in macrophages, endothelial cells, and arterial smooth cells to favor increased lipoprotein retention, sterol content, and inflammatory response in the vessel wall. These changes in the vessel wall favor growth of the atherosclerotic plaque and may predispose to instability and plaque rupture.

Figure 3. The intersection of inflammation, T2DM and atherosclerosis

Important relationships among inflammation, atherosclerosis, and key characteristics of T2DM are shown. Sorting out mechanistic relationships in humans is challenging given the chronicity of these problems, including relatively long pre-clinical phases and common, overlapping antecedents, like increased insulin resistance. For example, the constellation of abnormalities associated with T2DM, and pre-diabetic states, are also associated with cardiovascular risk. One common theme in these connections is inflammation.

Figure 4. Macrophage biology in T2DM and atherosclerosis

The macrophage is a key player in atherosclerosis and may play an important role in the accelerated atherosclerosis of diabetes. Various factors commonly encountered in T2DM – hyperglycemia, elevated circulating cytokokines, increased free fatty acids (FFA), LDL and its modified forms, AGEs and cellular debris in the arterial wall (e.g. apoptotic bodies) can incite multiple responses in macrophages, including ER stress, generation of reactive oxygen species (ROS), and increased ceramide levels. These and other stressors can impinge on downstream inflammatory signaling pathways, such as JNK/AP1 and NFκB, further amplifying expression of a pro-inflammatory macrophage phenotype. Other mechanisms, like PPARγ activation, may balance some of these inflammatory responses.