Insulin resistance, hyperglycemia, and atherosclerosis

Abstract

Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease.

Figure 1. Possible mechanisms through which insulin resistance in ECs, SMCs, and macrophages promotes atherogenesis

In early-mid-stage atherosclerotic lesions, insulin resistance is associated with a decrease in eNOS activation and NO production and increase in VCAM-1 expression by arterial ECs. Both of these perturbations may be due to down-regulation of the insulin receptor-Akt1 pathway in ECs. The net effect is endothelial dysfunction and activation, leading to defective vasodilation and increased entry of inflammatory cells into the plaque. Inset, summary scheme of canonical insulin receptor signaling pathway; see text for details.

Figure 2. Possible mechanisms through which insulin resistance in ECs, SMCs, and macrophages promotes advanced plaque progression

In advanced plaques, insulin resistance may promote apoptosis of all three major cell types. Death of SMCs can lead to fibrous cap thinning, while death of macrophages, coupled with defective phagocytic clearance of the cells (efferocytosis), promotes plaque necrosis. Both fibrous cap thinning and plaque necrosis can precipitate plaque rupture and acute thrombotic vascular occlusion. Not shown in this scheme is the possibility that elevated saturated fatty acids associated with obesity and insulin resistance causes defective efferocytosis of apoptotic macrophages.

Figure 3. Possible mechanisms through which hyperglycemia in ECs, VSMCs, and macrophages promotes atherogenesis

Hyperglycemia may accelerate formation of early/mid stage lesions of atherosclerosis by promoting adhesion molecule expression in ECs through epigenetic changes, increased flux through the AR pathway, and maybe through activation of PKC, RAGE, and increased reactive oxygen species (ROS) levels. Increased adhesion molecule expression leads to increased monocyte/macrophage accumulation and atherogenesis. In VSMCs, a principal effect of increased glucose uptake appears to be increased secretion of the chemokine MCP-1, which could act in concert with the EC changes to bring more monocytes into the growing lesion. Hyperglycemia also promotes an inflammatory phenotype in macrophages, which most likely further contributes to early atherogenesis. The effects of hyperglycemia on both ECs and macrophages are most pronounced in the presence of an inflammatory environment.