From:  Disruption of the transsulfuration pathway as a sulfur-driven etiology of insulin resistance: proinsulin misfolding, disulfide bond deformation, and PDI dysregulation

 Structural evidence of disulfide bond disruption and insulin misfolding.

YearStudy (authors)Model/ApproachFindingsQuantitative dataInterpretation
2017van Lierop et al. [97]Structural biochemistryDisulfide bonds regulate folding, protect degradation, and enable receptor activation—S-S bonds critical for bioactivity
2015Vinther et al. [98]Engineered insulin analogAdded disulfide bond ↑ stability, no loss of function—Confirms stabilizing role of extra S-S
2003–2021Chang et al. [100]; Jarosinski et al. [99]; Ong et al. [101]Synthetic analogs w/A6–A11 disruption↓ Receptor binding affinity50–70% lossDisruption severely impairs function
2019–2024Hubálek et al. [102]; Zheng et al. [103]; Weil-Ktorza et al. [104]Replacement of A6–A11Thioacetal/Diselenide bonds ↑ foldability & resistance—Alternative bonds protect insulin
2005Yoshinaga et al. [105]Mutation studies (A7–B7, Ins2Akita)↓ Receptor affinity, ↓ PI3K-Akt signaling—A7–B7 are essential for insulin action
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PI3K-Akt: phosphoinositide 3-kinase-protein kinase B.