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

 Emerging in vivo evidence of disulfide bond instability and insulin chain splitting.

YearStudy (Authors)Model/DesignFindingsQuantitative dataInterpretation
2024Cramer et al. [113]Human plasma (HI 1 µM, 80% plasma, 37°C)Insulin chain splitting via thiol-disulfide exchange97.5% intact HI lost by 169 h; LC-MS confirmed free A & B chainsPlasma reductive stress destabilizes insulin
2024Cramer et al. [113]Rat clamp (HI 2 nmol/kg/min)A-chain detected in plasmaRelease rate ~0.40 nmol/kg/min (~20% infusion)In vivo chain splitting occurs
2024Cramer et al. [113]Mechanistic paradoxIV insulin remains effectiveDue to the bypass of hepatic portal redox stressEndogenous insulin is more vulnerable than exogenous insulin

HI: human insulin; IV: intravenous; LC-MS: liquid chromatography-mass spectrometry.