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 afflict over 700 million individuals by 2045, demands a revolutionary etiological paradigm. The Sulfur Insulin Deformation Hypothesis redefines T2DM as a sulfur metabolism disorder driven by insulin misfolding due to organic sulfur deficiency, rooted in mitochondrial dysfunction in intestinal epithelial cells. This deficiency disrupts transsulfuration pathways, slashing cysteine and glutathione levels by 30–73.8% (red blood cell glutathione: 1.78 ± 0.28 vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001), amplifying reactive oxygen species (ROS) and lipid peroxides. This redox imbalance impairs protein disulfide isomerase (PDI) activity, notably PDIA1, PDIA3, and PDIA4, disrupting insulin’s critical disulfide bonds (A6–A11, A7–B7, A20–B19), essential for receptor-binding affinity. Disruption of the A6–A11 hinge bond reduces affinity by 50–70% (r = -0.65, P < 0.05 for HOMA-IR), crippling PI3K-Akt signaling and glucose transporter type 4 (GLUT4) translocation, driving hyperglycemia. Elevated PDIA4 levels in 225 T2DM patients (P < 0.001) correlate with fasting glucose (r = 0.62, P < 0.01) and reduced insulin sensitivity (r = -0.67, P < 0.01). PDIA4 inhibition by PS1 (IC50 = 4 μM) cuts 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 elevates proinsulin/insulin ratios (P < 0.01), while PDIA3-driven RhoA-YAP signaling fuels adipose inflammation (P < 0.05). N-acetylcysteine (NAC) and GlyNAC restore glutathione by 20–40% (P < 0.01) and insulin sensitivity by 31% (P < 0.05). Aberrant S-nitrosylation further disrupts disulfide bonds, exacerbating insulin resistance. This hypothesis proposes that insulin resistance in T2DM may arise from insulin misfolding due to disrupted disulfide bonds (A6–A11, A7–B7, A20–B19) and PDI dysregulation, revolutionizing therapeutic strategies targeting the gut-mitochondria-sulfur-insulin axis.