Atherosclerosis and Insulin Resistance: Is There a Link Between Them?

Abstract

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, especially in regions like Eastern Europe, South Asia, and Latin America. A significant portion of these cases (80%) is linked to atherosclerosis, which can lead to severe conditions like ischemic heart disease and stroke, with atherosclerosis (ATS) responsible for the majority of cases. This review explores the multifaceted relationship between insulin resistance (IR) and ATS, highlighting their roles as both independent and interrelated contributors to cardiovascular risk. ATS is characterized by lipid accumulation and chronic inflammation within arterial walls, driven by factors such as hypertension, dyslipidemia, and genetic predisposition, with endothelial dysfunction as a key early event. The early detection of subclinical ATS is critical and can be achieved through a combination of non-invasive imaging techniques-such as coronary artery calcium scoring and carotid ultrasound-and comprehensive risk profiling. IR, marked by impaired glucose uptake in liver, muscle, and adipose tissue, often precedes early diabetes and is associated with metabolic disturbances, including dyslipidemia and chronic inflammation. The diagnosis of IR relies on surrogate indices such as HOMA-IR, the QUICKI, and the TyG index, which facilitate screening in clinical practice. Compelling evidence indicates that IR independently predicts the progression of atherosclerotic plaques, even in non-diabetic individuals, and operates through both traditional risk factors and direct vascular effects. Understanding and targeting the IR-ATS axis is essential for the effective prevention and management of cardiovascular disease.

Keywords: cardiovascular risk; endothelial dysfunction; insulin resistance; subclinical atherosclerosis.

Figure 1

The connection between insulin resistance and atherosclerosis development and progression. Insulin resistance triggers gluconeogenesis since glucose uptake mediated by GLUT-3 is impaired. At the muscle level, due to impaired GLUT-2/4-mediated glucose uptake, glucose utilization is impaired. At the adipose tissue level, lipolysis is increased and adipokine secretion is altered, leading to a metabolic impairment characterized by hyperglycemia, initial hyperinsulinemia, increased LDL-cholesterol and trigyliceride levels, and reduced serum high-density lipoprotein (HDL)-cholesterol. In clinical practice, the TyG index is widely used as a screening method for insulin resistance. Alongside the TyG index, other indices such as the homeostasis model assessment of insulin resistace (HOMA-IR), the triglyceride/HDL-cholesterol ratio (TG/HDLc), and the quantitative insulin sensitivity check index (QUICKI) have also proved their utility in insulin resistance screening. Increased low-density lipoprotein (LDL)-cholestrol levels, in the presence of cardiovascular risk factors, leads to endothelial dysfunction and subsequent modifications of LDL-cholesterol particles, such as oxidation and desialylation, triggering a macrophage-mediated immune response. The most widely used paraclinical test for diagnosing subclinical atherosclerosis is coronary computed tomography (CT) angiogram (with calcium scoring), also suggested by the actual guidelines for improved risk stratification in coronary artery disease (CAD). Created in BioRender. Tirziu, A. (2025) https://BioRender.com/2wkbiot (accessed on 20 May 2025).

Figure 2

Endothelial dysfunction promotes the infiltration of ApoB-containing lipoproteins (LDLs) into the arterial wall, where they undergo oxidative modification (oxLDL) via reactive oxygen species (ROS). OxLDL triggers the recruitment of monocytes through the upregulation of adhesion molecules (ICAM-1, VCAM-1). Monocytes differentiate into resident and M1 macrophages, which engulf oxidized LDL (oxLDL) to form foam cells. Pro-inflammatory cytokines (IFN-γ, TNF-α) secreted by Th1 lymphocytes further activate M1 macrophages, amplifying inflammation. Foam cell apoptosis and the secretion of proteases such as cathepsin S and MMP-9 contribute to extracellular matrix (ECM) degradation, the thinning of the fibrous cap, and the expansion of the lipid necrotic core. Cholesterol crystals released from dying foam cells activate the NLRP3 inflammasome, leading to increased secretion of IL-1β and IL-18, which further recruit inflammatory cells and perpetuate vascular inflammation. The dysregulation of T cell subsets-characterized by increased Th1 and Th17 lymphocytes and decreased regulatory T cells (Tregs) exacerbates inflammation, disrupts anti-inflammatory responses, and promotes plaque instability and thrombus formation. Created in BioRender. Tirziu, A. (2025) https://BioRender.com/lcalh3v (accessed on 20 May 2025).