Sulfur-Dependent Misfolding of Insulin as a Root Cause of Type 2 Diabetes: A Hypothesis Centered on Disulfide Bond Disruption at A6–A11, A7–B7, and A20–B19 in the Etiology of Insulin Resistance

Type 2 diabetes mellitus (T2DM), projected to affect over 700 million people by 2045, necessitates a transformative etiological perspective. The Sulfur Insulin Deformation Hypothesis redefines T2DM as a sulfur metabolism disorder driven by insulin misfolding due to organic sulfur deficiency, originating from mitochondrial dysfunction in intestinal epithelial cells. Evidence demonstrates 30–73.8% reductions in cysteine and glutathione levels in T2DM patients (RBC glutathione: 1.78 ± 0.28 vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001), driven by impaired transsulfuration pathways (cystathionine β-synthase, γ-lyase) and elevated oxidative stress (increased ROS, lipid peroxides). This redox imbalance inhibits protein disulfide isomerase (PDI), an endoplasmic reticulum enzyme critical for forming and isomerizing insulin’s disulfide bonds: A6–A11 (intra-A-chain, stabilizing α-helical core), A7–B7 (interchain, anchoring A- and B-chains), and A20–B19 (interchain, enabling receptor-binding conformation). Disruption of the A6–A11 hinge bond reduces insulin receptor affinity by 50–70% (r = -0.65, P < 0.05 for HOMA-IR), impairing PI3K-Akt signaling, GLUT2/GLUT4 translocation, and promoting gluconeogenesis, sustaining hyperglycemia. Cysteine deficiency activates NF-κB and JNK, elevating pro-inflammatory cytokines (TNF-α, IL-6), exacerbating insulin resistance via serine phosphorylation. Impaired mucin synthesis weakens the gut barrier, triggering TLR4-mediated endotoxemia and SOCS-driven inflammation. Interventions like N-acetylcysteine (NAC) and GlyNAC restore glutathione by 20–40% (P < 0.01), improve insulin sensitivity by 31% (P < 0.05), and enhance mitochondrial fatty acid oxidation. This model explains hyperinsulinemia alongside hyperglycemia, as misfolded insulin accumulates but fails to signal, while exogenous insulin restores function. This hypothesis proposes that insulin resistance and T2DM stem from insulin’s structural deformation due to disrupted disulfide bonds (A6–A11, A7–B7, A20–B19), mediated by impaired PDI function.