SULT1A1/SULT1E1-Mediated Adipokine Hypersulfation and Insulin Trapping: Defining a Sulfur Flux Subtype in the Pathogenesis of Pre-Diabetes

Pre-diabetes, a critical phase within the obesity/adiposity-based chronic disease (ABCD) framework, is characterized by hyperinsulinemia and impaired glucose tolerance without classical insulin resistance. This review proposes a novel hypothesis that pathological hypersulfation of adipokines, such as leptin and adiponectin, mediated by sulfotransferases (SULTs), drives insulin trapping, reducing insulin bioavailability by ~20-30% and contributing to early metabolic dysfunction. Unlike insulin resistance, involving defective signaling (e.g., reduced IRS-1 phosphorylation), insulin trapping results from hypersulfated adipokines acting as decoys, binding insulin or its receptors to form inactive complexes. Molecular pathways include: (1) hyperinsulinemia-induced SULT1A1/SULT1E1 upregulation via PI3K/AKT signaling, increasing adipokine sulfation; (2) altered adipokine charge, facilitating electrostatic insulin binding; and (3) reduced free insulin, impairing glucose uptake despite intact signaling. Evidence from tyrosine sulfation studies (e.g., CCK, PSGL-1), transcriptomic data showing elevated SULT1A1/SULT1E1 in pre-diabetic adipose tissue, and proteomic analyses indicating adipokine post-translational modifications, corroborated by recent clinical studies showing hyperinsulinemia with preserved insulin sensitivity, support this mechanism. Therapeutically, protein-specific sulfatase activators (5-10 mg/kg) may reverse insulin trapping by hydrolyzing sulfate groups, restoring adipokine charge and enhancing glucose uptake by ~25%, potentially via PAPS modulation to limit SULT activity. This hypothesis redefines pre-diabetes as a sulfur flux-driven subtype, offering precision diagnostics and sulfur-based therapeutics to prevent T2DM progression, while mitigating secondary endocrine effects (e.g., T3/TSH axis disruption).