Metabolic and inflammatory axes of insulin resistance in normoglycemic adults with high HIV burden

Insulin resistance (IR) precedes type 2 diabetes and drives cardiovascular risk, but its early features in normoglycemic individuals remain unclear. The main goal of the study was to characterize multifactorial determinants of IR in normoglycemic adults. We conducted a retrospective cross-sectional analysis of a census of 100 normoglycemic adults (median age 44 years, interquartile range (IQR): 35-49), 70% (70/100) of whom were living with HIV and 65% (65/100) were obese (body mass index (BMI) ≥30 kg/m²). Fasting blood samples were profiled for amino acids, adipokines, and inflammatory markers using mass spectrometry and immunoassays. IR was assessed as a continuous variable using the Homeostatic Model Assessment of IR version 2 (HOMA2-IR). Multivariable linear regression identified independent factors associated with IR, stratified by obesity and adjusted for age and sex. In the overall cohort, the prevalence of IR was 36%. The adjusted analysis revealed leptin (β = 0.041, p = 0.009), triglycerides (β = 0.007, p = 0.006), glutamic acid (β = 0.025, p = 0.0001) and tyrosine (β = 0.029, p = 0.0004) were independently associated with IR. Mitochondrial-metabolically associated factors were dominant: propionylcarnitine (C3uM) (β = 4.727, p = 0.004), isoleucine (β = 0.051, p < 0.0001), glutamic acid (β = 0.035, p = 0.0001), and leptin (β = 0.097, p < 0.0001). Inflammation and dyslipidemia were mild determinants in the adjusted model: interleukin-6 (IL-6)(β = 0.274, p = 0.0003), interleukin-17 (IL-17) (β = 0.009; p = 0.004), tumor necrosis factor-alpha (TNF-α)(β = 0.337, p = 0.001), monocyte chemoattractant protein-1 (MCP-1)(β = 0.003; p = 0.005), fasting TG (β = 0.007; p = 0.006) and leptin (β = 0.041; p = 0.009). Glycine showed an inverse association (β = -0.005; p = 0.006). Two IR phenotypes emerged: metabolic, characterized by impaired branched-chain amino acid catabolism, elevated C3uM levels, which implicates mitochondrial overload and gut-derived metabolic flux as early drivers of IR, and inflammatory-lipotoxic, associated with adipose cytokine release in HIV infection, necessitating distinct biomarkers for early detection and individualized intervention.