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

Type 2 diabetes (T2D), the most common form of diabetes, is associated with a significantly elevated risk of cardiovascular and cerebrovascular complications. However, circulating metabolic signatures that reliably predict the transition to insulin resistance, and are potentially linked to increased vascular risk, remain incompletely characterized. Rodent models, particularly those induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), are widely used to study the progression of T2D. However, the systemic metabolic shifts associated with this model, especially at the plasma level, are poorly defined.

In this study, we performed untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomic profiling on plasma samples from control, HFD-only (obese, insulin-sensitive), and HFD + STZ (obese, insulin-resistant) C57BL/6 mice.

In the HFD + STZ cohort, plasma profiles showed a global shift toward lipid classes; depletion of aromatic and branched-chain amino acids (BCAAs); accumulation of phenylalanine-derived co-metabolites, consistent with gut-liver axis dysregulation; elevations in glucose, fructose-6-phosphate, and nucleoside catabolites, indicating impaired glucose handling and heightened nucleotide turnover; increased free fatty acids, reflecting membrane remodeling and lipotoxic stress; and higher cAMP, thyroxine, hydrocortisone, and uric acid, consistent with endocrine and redox imbalance. By contrast, HFD-only mice exhibited elevations in aromatic amino acids and BCAAs relative to controls, a pattern compatible with early obesity-associated adaptation while insulin signaling remained partially preserved. KEGG analysis revealed disturbances in carbohydrate metabolism, amino acid degradation, nucleotide turnover, and hormone-related pathways, and HMDB mapping linked these changes to T2D, obesity, heart failure, and renal dysfunction.

Collectively, these findings delineate insulin resistance-specific plasma signatures of metabolic inflexibility and inflammatory stress in the HFD + STZ model, distinguishing it from HFD alone and supporting its utility for mechanistic studies and biomarker discovery. Importantly, this plasma metabolomics study shows that insulin-sensitive and insulin-resistant states exhibit distinct variation in circulating metabolites and cardiovascular risk factors, underscoring the translational value of plasma profiling.