Compartment-specific Metabolic Alterations to Insulin Reflect Adiposity-driven Variation and Predict Type 2 Diabetes.

Area of Science:

• Metabolomics
• Endocrinology
• Diabetes Research

Background:

• Insulin resistance (IR) mechanisms remain unclear.
• Metabolomic profiling offers insights into compartment-specific metabolic variations.
• Identifies individuals at risk for type 2 diabetes (T2D).

Purpose of the Study:

• Characterize insulin-induced metabolomic changes during hyperinsulinemic-euglycemic clamp.
• Evaluate a derived risk score's predictive value for T2D.

Main Methods:

• Clamp studies in 80 adults (38 with T2D, 42 without) measured plasma and muscle metabolites.
• Developed and tested an IR metabolomic score in a prospective case-control study (367 cases, 910 controls) from the Women's Health Initiative.

Main Results:

• Hyperinsulinemia altered 79.5% of plasma metabolites (fatty acids, lactate, pyruvate) and 15.8% of muscle metabolites (amino acids).
• T2D associated with higher triglycerides and lower tricarboxylic acid intermediates during clamp.
• Adiposity amplified insulin-induced plasma lipid increases; risk score predicted incident T2D (HR 1.20 per SD).

Conclusions:

• Compartment-specific metabolic responses to insulin are influenced by adiposity.
• Metabolomic signatures predict future T2D risk.
• Supports using metabolomic signatures for early T2D identification and prevention.