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

 Clinical and biochemical evidence linking cysteine deficiency, GSH depletion, and redox imbalance to insulin dysfunction in T2DM patients.

YearStudy (authors)Sample/DesignQuantitative findingsEffect/Interpretation
2011Sekhar et al. [91]12 T2DM (HbA1c > 7%) vs. controlsRBC GSH ↓ 73.8% (1.78 ± 0.28 µmol/g vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001); ↓ plasma cysteine/glycine; ↑ ROS & lipid peroxidesSevere GSH depletion impairs insulin disulfide bonds
2014Jain et al. [92]79 T2DM↓ Cysteine & GSH; correlation r = 0.81 (P = 0.001); inverse w/HOMA-IR r = –0.65 (P < 0.05)Cysteine strongly predicts insulin sensitivity
2018Lutchmansingh et al. [93]16 T2DM (7 no complications, 9 w/microvascular)GSH ↓ (0.35 ± 0.30 mmol/L vs. 0.90 ± 0.42 mmol/L, P < 0.01); synthesis ↓ (0.50 ± 0.69 mmol/L/day vs. 1.03 ± 0.55 mmol/L/day, P < 0.05)Complications exacerbate sulfur deficiency
2016Gawlik et al. [96]Cross-sectional, T2DMRBC GSH NS (0.87 µmol/L vs. 0.92 µmol/L) but GPx ↓ (P < 0.05), ↑ malondialdehydeOxidative stress consumes GSH
2022Kalamkar et al. [94]RCT, 250 T2DM, 6 monthsOral GSH ↑ plasma GSH, ↓ 8-OHdG (P < 0.01), ↓ HbA1c especially in > 55 yearLong-term sulfur repletion improves HbA1c & insulin sensitivity
2024Tuell et al. [95]Pilot, T2DM, 14 day GlyNAC↑ RBC GSH (P < 0.01); ↑ insulin sensitivity +31% (P < 0.05); ↑ FAOShort-term sulfur donor restores insulin function
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8-OHdG: 8-hydroxy-2’-deoxyguanosine; GSH: glutathione; RBC: red blood cell; ROS: reactive oxygen species; T2DM: type 2 diabetes mellitus; GlyNAC: glycine and N-acetylcysteine; HbA1c: hemoglobin A1c; HOMA-IR: homeostatic model assessment of insulin resistance.