Metabolic and biochemical profiling reveals phenotypic heterogeneity in Zucker diabetic fatty rats

Zucker diabetic fatty (ZDF) rats exhibit significant phenotypic variability despite genetic uniformity, yet a comprehensive characterization of these divergent phenotypes remains limited.

Male ZDF (fa/fa) rats (4 months, n = 22) and ZDF (fa/+) lean controls (n = 10) were maintained on standard chow for 6 months. Based on metabolic trajectory, ZDF (fa/fa) rats were stratified into three phenotypes: obese normoglycemic (O, n = 8), diabetic with cachexia (D, n = 8), and diabetic without cachexia (D-C, n = 6). Comprehensive assessments included body weight, glycemic control, hepatic function, oxidative stress markers, and inflammatory cytokines.

Principal coordinate analysis confirmed significant metabolic separation between phenotypes (p < 0.01). Diabetic cachectic (D) rats exhibited severe hyperglycemia (>25 mmol/L), insulin depletion, elevated hepatic enzymes (alanine aminotransferase [ALT] increased 2.5-fold, p < 0.01), elevated interleukin-6, and delayed pain response. Diabetic rats without cachexia (D-C) exhibited intermediate hyperglycemia (≈13 mmol/L, p < 0.001 vs. control) with preserved insulin levels, and elevated fibroblast growth factor 21 (FGF21) and soluble receptor for advanced glycation end products (sRAGE). Obese normoglycemic (O) rats maintained normoglycemia with hyperinsulinemia and elevated triglycerides.

Under identical genetic and environmental conditions, ZDF (fa/fa) rats develop distinct metabolic phenotypes encompassing euglycemic obesity, pre-cachectic diabetes, and advanced cachectic diabetes. Phenotypic stratification is essential for accurate interpretation of ZDF experimental data and underscores the importance of characterizing individual metabolic trajectories when diabetic complications and therapeutic interventions are assessed in this model.