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Core Viewpoint - Insulin resistance (IR) is a critical mechanism in the development of type 2 diabetes mellitus (T2DM) and is associated with various metabolic disorders and cardiovascular diseases. Improving IR is essential for diabetes prevention and management [2][23]. Summary by Sections Definition and Metabolic Hazards of Insulin Resistance - Insulin resistance is defined as the inability of insulin to effectively stimulate glucose uptake in peripheral tissues and suppress hepatic glucose output. It is significantly negatively correlated with metabolic health indicators such as triglycerides and blood pressure [2]. - A study involving 1,326 T2DM patients found that for every 1 unit increase in HOMA-IR, the risk of cardiovascular events increased by 56%. Additionally, improving insulin resistance can reduce the risk of myocardial infarction by 42% [4]. Mechanisms of Insulin Resistance - Insulin resistance is primarily driven by energy surplus and includes mechanisms such as: - Adipocyte hypertrophy and overflow leading to elevated free fatty acid (FFA) levels [5]. - Chronic low-grade inflammation due to lipid overload, damaging insulin signaling pathways [6]. - Interference in signaling pathways by FFA and cytokines, particularly affecting GLUT4 transport systems [7]. - Decreased adiponectin levels, which diminishes insulin responsiveness [8]. Multi-Mechanism Action of Semaglutide in Improving Insulin Resistance - Semaglutide, a GLP-1 receptor agonist, improves insulin resistance through several mechanisms: - Appetite suppression and reduced energy intake, as shown in a study with 30 obese adults [9]. - Reduction of fat mass and improvement in lipid metabolism, with clinical studies indicating a 3.5 kg reduction in fat tissue and up to 17% reduction in visceral fat in diabetic patients [10]. - Increased adiponectin levels and suppression of inflammatory factors, demonstrating significant anti-inflammatory effects [11]. - Activation of GLUT-4 expression, enhancing glucose uptake and utilization [12]. - Significant reduction in HOMA-IR, with a 1.35% decrease in the GLP-1RA treatment group compared to an increase in the control group [13]. Inclusion of Semaglutide in Guidelines and Consensus - Semaglutide is recommended in various expert consensus documents for its ability to significantly improve insulin resistance, particularly in elderly diabetic patients [14]. - Additional recommendations highlight its use in cold climates where insulin resistance may be exacerbated [16]. - The ADA guidelines also list GLP-1RA as a preferred treatment for overweight/obese diabetic patients [18]. Clinical Treatment Recommendations and Individualized Management - Treatment strategies to improve insulin resistance include prioritizing GLP-1RA and SGLT2 inhibitors for their dual benefits on heart and kidney protection [19]. - Nutritional and exercise interventions are advised to control caloric intake and enhance muscle mass [20]. - Risk management for medications like insulin or thiazolidinediones is crucial to avoid complications [21]. - A multidimensional assessment of insulin resistance should be conducted using HOMA-IR, biochemical indicators, BMI, and waist-to-hip ratio [22]. Conclusion - Insulin resistance is a core pathological mechanism in T2DM and various metabolic disorders. Semaglutide, as a representative GLP-1RA, significantly improves insulin resistance through multiple pathways, making it a vital treatment option for T2DM patients, especially those with obesity and cardiovascular risks [23].