**Background:** Insulin resistance (IR) is a complex pathophysiological condition characterized by reduced tissue responsiveness to insulin, impaired glucose regulation, and compensatory hyperinsulinemia. It serves as a critical risk factor and pathogenic mechanism for numerous metabolic diseases including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and certain cancers. The global prevalence of IR and metabolic syndrome is substantial, with diabetes affecting 536.6 million people worldwide (10.5% of adults), projected to reach 783.2 million (12.2%) by 2045. Among T2DM patients, the global prevalence of NAFLD is 55.5% (95% CI 47.3-63.7), and up to 50% of hypertensive patients have NAFLD. This review aims to comprehensively examine the role of IR across metabolic diseases, its pathogenic mechanisms, and therapeutic approaches.
**Methods:** This is a narrative review synthesizing evidence from clinical studies, epidemiological data, animal experiments, and molecular research on IR. The authors searched relevant literature covering IR pathogenesis, its relationship with metabolic diseases, and treatment strategies. The review integrates findings from multiple levels including genetic, molecular, cellular, and clinical perspectives.
**Key Results:** The paper identifies IR as a central mechanism linking multiple metabolic diseases. For diabetes, IR is present in both T1DM and T2DM, with the triglyceride-glucose index (TyG index) serving as a convenient measure associated with higher risk for lower extremity macrovascular stenosis, arterial stiffness, and renal microvascular injury. IR accounts for approximately 42% of myocardial infarctions, making it potentially the most important single cause of coronary artery disease. In NAFLD, high IR is the most important predictor in both obese and lean subjects, with serum insulin levels strongly associated with hepatic lobular inflammation and histological progression. Among PCOS patients, 50% develop IR regardless of obesity.
The pathogenesis of IR involves multiple mechanisms: (1) Genetic factors including mutations in insulin, insulin receptor genes (causing syndromes like leprechaunism, Rabson-Mendenhall syndrome), and genes affecting GLUT4, glucokinase, and PPAR nuclear receptors. (2) Environmental factors, particularly obesity, where a 10% reduction in BMI improves IR. Waist circumference correlates closely with IR, and weight exceeding 35-40% of ideal body weight reduces tissue insulin sensitivity by 30-40%. (3) Molecular mechanisms including insulin receptor defects, abnormal insulin signaling through PI3K-AKT and MAPK pathways, inflammation mediated by TNF-α, IL-6, and CRP, activation of JNK and IKKβ/NF-κB inflammatory pathways, and immune cell dysregulation with M1/M2 macrophage polarization shifts. (4) Lipotoxicity from elevated free fatty acids, ceramide accumulation (which inhibits Akt/PKB activity through PP2A activation), and diacylglycerol accumulation activating novel PKC isoforms. (5) Organelle dysfunction including mitochondrial dysfunction, ER stress, and mitochondrial-associated membrane (MAM) imbalance. (6) Autophagy deficiency and gut microbiota dysbiosis, where Prevotella copri induces IR and increases circulating branched-chain amino acids.
Treatment approaches include lifestyle interventions (7-10% weight loss, 150 minutes of moderate exercise weekly), dietary modifications (Mediterranean diet, high-protein diet, 40-50% carbohydrate intake, increased fiber by 15-35 grams daily reducing HOMA-IR), and pharmacological treatments. Metformin remains first-line therapy, reducing new-onset diabetes by 40% across 31 RCTs. Thiazolidinediones (pioglitazone, rosiglitazone) act as PPARγ agonists, SGLT2 inhibitors improve insulin sensitivity through weight reduction and glucose toxicity reduction, and GLP-1 receptor agonists reduce inflammation and oxidative stress. Emerging therapies target PPAR-α/δ, NLRP3 inflammasome, gut microbiota, and include traditional Chinese medicine approaches.
**Clinical Implications:** IR should be considered a therapeutic target for patients with multiple metabolic comorbidities, enabling simultaneous treatment of several conditions with unified approaches. Early detection of IR using emerging biomarkers beyond current indices (HOMA, TyG index) is needed, though clinical validation remains required. Lifestyle modification remains the most fundamental and cost-effective intervention. The development of normative criteria for different metabolic diseases with IR as a focus could improve clinical management and reduce healthcare expenditures.