Plasma Metabolomic Profiling Reveals Systemic Alterations in a Mouse Model of Type 2 Diabetes

Area of Science:

• Metabolomics
• Biochemistry
• Endocrinology

Background:

• Type 2 diabetes (T2D) significantly increases cardiovascular and cerebrovascular risks.
• Circulating metabolic signatures predicting insulin resistance and vascular risk are not fully understood.
• Rodent models, like high-fat diet (HFD) + streptozotocin (STZ), are used for T2D research but their plasma metabolic profiles are poorly defined.

Purpose of the Study:

• To characterize systemic metabolic shifts in plasma using untargeted metabolomics.
• To differentiate metabolic profiles between control, HFD-only (obese, insulin-sensitive), and HFD + STZ (obese, insulin-resistant) mice.
• To identify insulin resistance-specific plasma signatures.

Main Methods:

• Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomic profiling.
• Analysis of plasma samples from C57BL/6 mice under control, HFD-only, and HFD + STZ conditions.
• KEGG and HMDB pathway analysis.

Main Results:

• HFD + STZ mice showed increased lipids, decreased amino acids, altered glucose handling, elevated free fatty acids, and hormonal/redox imbalance.
• HFD-only mice displayed elevated aromatic amino acids and branched-chain amino acids (BCAAs), indicating early obesity adaptation.
• Metabolic disturbances were linked to T2D, obesity, heart failure, and renal dysfunction.

Conclusions:

• Distinct plasma metabolomic signatures of metabolic inflexibility and inflammatory stress were identified in the HFD + STZ model.
• These signatures distinguish insulin resistance from HFD-induced obesity alone.
• Plasma metabolomics reveals differences between insulin-sensitive and resistant states, highlighting translational value for biomarker discovery and mechanistic studies.