Retinol-Binding Protein-4 and Cardiovascular Disease Risk in Type 2 Diabetes: A Review Article

Abstract

Type 2 diabetes mellitus (T2DM) is a major metabolic disorder characterized by insulin resistance, progressive β-cell dysfunction, chronic hyperglycemia, and a high burden of cardiovascular disease (CVD). Increasing evidence indicates that adipose tissue is an endocrine organ whose secretory products, or adipokines, participate in the metabolic and vascular abnormalities linking obesity and T2DM to cardiovascular complications. Retinol-binding protein 4 (RBP4) is a 21-kDa lipocalin traditionally recognized as the principal circulating carrier of retinol, but it is now also regarded as an adipokine with potential metabolic and cardiovascular actions. This review summarizes the biological characteristics of RBP4 and critically examines its relationships with obesity, visceral adiposity, insulin resistance, dyslipidemia, vascular inflammation, endothelial dysfunction, atherosclerosis, hypertension, coronary artery disease, heart failure, and diabetic cardiomyopathy. Mechanistically, RBP4 may influence glucose homeostasis through retinol-dependent pathways involving retinoic acid signaling and hepatic gluconeogenesis, while retinol-independent pathways may involve STRA6-related signaling, macrophage activation, Toll-like receptor pathways, JNK/NF-κB signaling, and inflammatory cytokine production. RBP4 has also been associated with atherogenic lipid profiles, macrophage foam-cell formation, oxidative stress, vascular smooth-muscle responses, impaired nitric-oxide signaling, and myocardial inflammatory injury. Human studies generally support associations between higher circulating RBP4 and cardiometabolic risk, although results are heterogeneous and may be influenced by adiposity distribution, renal function, metabolic status, assay methodology, and population characteristics. Therefore, RBP4 represents a biologically plausible and potentially useful biomarker of cardiometabolic risk, but its independent predictive value and therapeutic relevance require further prospective and mechanistic investigation.