Abstract
Obesity-induced insulin resistance is an escalating global health challenge that substantially contributes to the development of metabolic disorders, including type 2 diabetes mellitus and cardiovascular disease. This narrative review critically examines the molecular and cellular mechanisms linking excess adiposity to impaired insulin action, with a particular focus on adipose tissue dysfunction, chronic low-grade inflammation, and oxidative stress. A comprehensive literature search was conducted using PubMed, ScienceDirect, and Google Scholar, covering preclinical and clinical studies published primarily over the past two decades. Evidence indicates that adipocyte hypertrophy and hypoxia promote excessive free fatty acid release, ectopic lipid accumulation, and lipotoxicity, thereby disrupting insulin signalling pathways. Numerous clinical studies report that obesity triggers chronic, low-grade inflammation in the liver and pancreas, activating pathways such as NF-κB and SOCS proteins, thereby disrupting insulin signalling. Concurrently, obesity-associated inflammation drives immune cell infiltration and macrophage polarization toward a pro-inflammatory phenotype, further exacerbating insulin resistance and metabolic dysregulation. This review also synthesizes current therapeutic strategies targeting these mechanisms, including insulin-sensitizing agents, anti-inflammatory therapies, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors, as well as emerging approaches. Future perspectives highlight the growing relevance of personalized medicine, pharmacogenomics, digital health tools, and gene-based interventions in improving therapeutic precision. A deeper understanding of these interconnected pathways is essential for developing effective strategies to mitigate obesity-related insulin resistance and its global metabolic consequences. Graphical Abstract