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CONTEXT: The metabolic mechanisms underlying insulin resistance (IR) are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D).OBJECTIVE: To characterize insulin-induced metabolomic changes during a hyperinsulinemic-euglycemic clamp and evaluate a derived risk score's predictive value for T2D.DESIGN, SETTING, AND PARTICIPANTS: Clamp studies were conducted in 80 adults (38 with T2D, 42 without) to measure plasma and muscle metabolites in fasting and hyperinsulinemic states. An IR metabolomic score was developed and tested in a prospective case-control study (367 cases, 910 controls) from the Women's Health Initiative (28.5-year follow-up).MAIN OUTCOME MEASURES: Metabolite changes during hyperinsulinemia and incident T2D.RESULTS: Hyperinsulinemia altered 79.5% of plasma metabolites (notably fatty acids, lactate, pyruvate) and 15.8% of muscle metabolites (e.g., branched-chain and aromatic amino acids). T2D was associated with higher triglycerides and lower tricarboxylic acid intermediates during clamp. Adiposity amplified insulin-induced increases in plasma lipids. The risk score predicted incident T2D (HR 1.20 per SD; 95% CI: 1.09-1.32; P = 7.4 × 10⁻⁴).CONCLUSIONS: Compartment-specific metabolic responses to insulin are shaped by adiposity and predict future T2D risk, supporting use of metabolomic signatures for early identification and prevention.