The Sulfur Insulin Deformation Hypothesis: Disulfide Bond Disruption (A6–A11, A7–B7, A20–B19) and PDI Dysregulation as an Etiology of Insulin Resistance

Type 2 diabetes mellitus (T2DM), projected to affect over 700 million by 2045, requires a new etiological framework. The Sulfur Insulin Deformation Hypothesis redefines T2DM as a sulfur metabolism disorder, driven by mitochondrial suffocation in intestinal epithelial cells, disrupting transsulfuration pathways converting methionine to cysteine via cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL). Mitochondrial dysfunction impairs ATP, depleting cysteine and glutathione (GSH) by 30–73.8% (red blood cell GSH: 1.78 ± 0.28 vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001), boosting reactive oxygen species (ROS) and lipid peroxides. This redox imbalance disrupts protein disulfide isomerase (PDI) activity (PDIA1, PDIA3, PDIA4) in β-cell endoplasmic reticulum (ER), impairing insulin’s disulfide bonds (A6–A11, A7–B7, A20–B19). The A6–A11 hinge bond, vital for receptor affinity, loses 50–70% binding capacity upon disruption (r = -0.65, P < 0.05 for HOMA-IR), hindering PI3K-Akt signaling and GLUT4 translocation, causing hyperglycemia. Elevated PDIA4 in 225 T2DM patients correlates with fasting glucose (r = 0.62, P < 0.01) and reduced sensitivity (r = -0.67, P < 0.01). PDIA4 inhibition by PS1 (IC50 = 4 μM) reduces ROS by 50% (P < 0.01), improves HbA1c by 1.2% (P < 0.05), and boosts β-cell survival by 30% (P < 0.05). PDIA1 deletion raises proinsulin/insulin ratios (P < 0.01), while PDIA3-driven RhoA-YAP signaling drives adipose inflammation (P < 0.05). S-nitrosylation further disrupts disulfide bonds. New evidence highlights a secondary extracellular mechanism: redox-mediated chain splitting degrades 20% of circulating insulin (A-chain rate 0.40 nmol/kg/min) at ~ -137 mV plasma redox, modulated by GSH. This explains the paradox of effective intravenous (IV) insulin exogenous analogs bypass hepatic GSH clearance and resist splitting while misfolded endogenous insulin, destabilized by sulfur scarcity, succumbs to plasma thiol attacks. This hypothesis posits that insulin resistance arises from organic sulfur deficiency, inducing structural deformities via disrupted disulfide bonds (A6–A11, A7–B7, A20–B19) and impaired PDIA1, PDIA3, PDIA4 activity. It resolves the paradox of exogenous insulin efficacy, attributing it to structurally intact molecules, contrasting with deformed endogenous insulin. The secondary mechanism likely stems from sulfur deficiency elevating ROS and lipid peroxides, accelerating chain splitting. Sulfur donors like N-acetylcysteine (NAC, restoring GSH by 20–40%, P < 0.01), GlyNAC (improving sensitivity by 31%, P < 0.05), and methylsulfonylmethane (MSM, reducing oxidative stress by 25%) mitigate these defects, advocating therapies targeting the gut-mitochondria-sulfur-insulin axis.