Insulin resistance and atherosclerosis

Abstract

Insulin resistance characterizes type 2 diabetes and the metabolic syndrome, disorders associated with an increased risk of death due to macrovascular disease. In the past few decades, research from both the basic science and clinical arenas has enabled evidence-based use of therapeutic modalities such as statins and angiotensin-converting enzyme inhibitors to reduce cardiovascular (CV) mortality in insulin-resistant patients. Recently, promising drugs such as the thiazolidinediones have come under scrutiny for possible deleterious CV effects. Ongoing research has broadened our understanding of the pathophysiology of atherosclerosis, implicating detrimental effects of inflammation and the cellular stress response on the vasculature. In this review, we address current thinking that is shaping our molecular understanding of insulin resistance and atherosclerosis.

Figure 1. The Central Role of Insulin Resistance in Vascular Disease

Multiple environmental and genetic factors contribute to the formation of the insulin resistance phenotype (aka the “metabolic syndrome”), marked by hypertension, dyslipidemia, obesity, and glucose intolerance. These risk factors in turn contribute to initiation and progression of type 2 diabetes and the macrovascular diseases (i.e. myocardial infarctions, strokes, and peripheral vascular disease).

Figure 2. Critical Proatherogenic Signaling Events at the Vasculature in the Setting of Insulin Resistance

The secretion of proinflammatory mediators initiated by systemic insulin resistance stimulate several intracellular signaling cascades, of which NFκB and JNK (a member of the MAP kinase family) are prominent examples; these potent inducers of proinflammatory genes create a feedforward cycle of signaling that provokes several aspects of atherogenesis. In addition, insulin resistance also selectively interferes with PI-3-kinase-mediated insulin receptor signaling, in turn suppressing eNOS activity in favor of the proproliferative/proatherogenic MAP kinases. Finally, states of nutrient excess dysregulate mitochondrial energy balance thus promoting respiratory uncoupling and the generation of reactive oxygen species (ROS); this can wreak havoc on the integrity of the genome and blunt vascular defenses against atherogenesis.