Sulfur-Dependent Disulfide Bond Disruption in Insulin Resistance: A Hypothesis

To Editor, Type 2 diabetes mellitus (T2DM), projected to affect over 700 million individuals by 2045, is conventionally attributed to peripheral insulin resistance driven by obesity, inflammation, and impaired insulin signaling. 1We propose the Sulfur Insulin Deformation Hypothesis, a conceptual framework suggesting that insulin misfolding, potentially arising from organic sulfur deficiency, may disrupt the integrity of insulin's three disulfide bonds (A6-A11, A7-B7, A20-B19), thereby contributing to insulin resistance.This hypothesis proposes that T2DM may involve a sulfur metabolism disorder linked to mitochondrial dysfunction in intestinal epithelial cells, offering a novel perspective for further investigation into its pathogenesis.Insulin, a 51-amino-acid polypeptide comprising A (21 amino acids) and B (30 amino acids) chains, relies on three disulfide bonds formed through cysteine thiol oxidation to maintain its bioactive conformation and high-affinity binding to the insulin receptor (IR). 2,3In pancreatic beta cells, insulin biosynthesis begins with preproinsulin, which is cleaved to proinsulin and folded in the endoplasmic reticulum (ER).Protein disulfide isomerase (PDI) facilitates disulfide bond formation, a process dependent on cysteine availability. 4The A6-A11 bond, acting as a dynamic hinge, aligns critical residues (e.g., ValA3, TyrA19) for IR docking, while A7-B7 and A20-B19 stabilize the hydrophobic core. 5,6Disruption of these bonds, particularly A6-A11, may reduce IR affinity by 50-70%, potentially impairing phosphoinositide 3-kinase (PI3K)-Akt signaling and glucose transporter type 4 (GLUT4) translocation, which could contribute to hyperglycemia. 7,8his hypothesis suggests that mitochondrial dysfunction in intestinal epithelial cells may impair the transsulfuration pathway (involving cystathionine -synthase and -lyase), potentially reducing cysteine synthesis. 9Such cysteine deficiency could limit glutathione production, a critical antioxidant, by 30-73.8% in T2DM patients.