Integrative Metabolomics of Targeted and Nontargeted Analyses in T2D Progression

Area of Science:

• Metabolomics
• Endocrinology
• Human Physiology

Background:

• Type 2 diabetes (T2D) development involves complex metabolic dysregulation.
• Identifying stage-specific metabolic alterations is crucial for understanding disease progression from normal glucose metabolism (NORM) to prediabetes (PreT2D) and T2D.

Purpose of the Study:

• To identify stage-specific metabolites characterizing the progression from NORM to PreT2D and T2D.
• To investigate early (NORM to PreT2D) and late (PreT2D to T2D) metabolic shifts.
• To explore the mechanistic and causal relevance of identified metabolites.

Main Methods:

• Analysis of 8,240 observations from the KORA cohort with longitudinal metabolite profiling (targeted and non-targeted).
• Trajectory analyses identified incident PreT2D and T2D cases over 14 years.
• Linear mixed-effects models, mediation, and Mendelian randomization (MR) analyses were employed.

Main Results:

• 140 significant metabolites were identified, including 68 early-stage markers (e.g., lipids, TCA cycle metabolites) and 20 late-stage markers (e.g., BCAAs, γ-glutamyl derivatives).
• Fasting glucose partially mediated the association between γ-glutamyl-valine and T2D.
• MR analysis did not support causal roles for BCAAs or γ-glutamyl-valine in T2D.

Conclusions:

• Early diabetes progression is characterized by shifts in energy metabolism.
• Later stages of diabetes involve alterations in amino acid metabolism.
• Stage-specific metabolic signatures offer potential targets for diabetes prevention.