Sulfur-donor therapies (NAC, MSM, and combined NAC + MSM) for type 2 diabetes: mechanisms, evidence, dosage, and translational considerations.
| Compound/Strategy | Mechanistic targets | Clinical & preclinical evidence | Typical dosage (oral, under supervision) | Strengths | Limitations | Future directions |
|---|---|---|---|---|---|---|
| NAC | Cysteine precursor → ↑ GSH synthesis via GCL & GS [78–80]Supports PDI → correct insulin disulfide bond formation (A6–A11, A7–B7, A20–B19) [81]Inhibits JNK → restores IRS-1/PI3K/Akt/GLUT4 signaling [82–84]Suppresses NF-κB → ↓ TNF-α, IL-6 [85]Reinforces gut barrier integrity (occludin, ZO-1, TLR4-LPS axis) [86, 87] | Sekhar et al. [91], 2011: restored GSH in T2DM [78]; Jain et al. [92], 2014: cysteine & vitamin D correlated with GSH/insulin sensitivity [79]; Kalamkar et al. [94], 2022: RCT, improved HbA1c and GSH [80] | 600–1,200 mg/day | Well-studied antioxidantTargets oxidative stress, ER stress, inflammation, and gut barrier | Most studies are small-scale (≤ 250)Short follow-up (≤ 6 months)No direct insulin structure confirmation | Long-term RCTs (≥ 12 months) with structural insulin assays (LC-MS/MS) |
| MSM | Bioavailable sulfur donor [88]Enhances CBS & CGL activity → ↑ cysteine via transsulfuration [88]Supports GSH synthesis & PDI folding of insulin [88]Inhibits NF-κB → ↓ pro-inflammatory cytokines [89]Improves gut barrier & reduces TLR4-mediated inflammation [89] | Butawan et al. [89], 2017: safety, anti-inflammatory benefits. Preclinical studies: redox & mitochondrial improvements [88, 89] | 1,000–3,000 mg/day | Safe dietary supplementsDirect sulfur replenishment | Human T2DM data are scarceNo long-term clinical trials | Pilot RCTs in T2DMBiomarker studies for insulin folding & receptor binding |
| NAC + MSM (combined protocol) | Dual sulfur sources: NAC (cysteine precursor) + MSM (direct sulfur donor) [90]Synergistic ↑ cysteine & GSHStronger PDI activity → stabilizes insulin folding [81, 88]Inhibits JNK & NF-κB pathways concurrently [82–85, 89]Reinforces intestinal barrier & ↓ TLR4-driven systemic inflammation [86–89] | Hypothesis-driven framework (Sulfur-Insulin Deformation Hypothesis) [78–90]. Rationale: complementary sulfur replenishment mechanisms → broader redox & metabolic correction | NAC 600–1,200 mg/day + MSM 1,000–3,000 mg/day | Multi-targeted approach (redox, ER stress, cytokine storm, gut barrier)Potential synergistic efficacy vs. monotherapy | No direct clinical trial of NAC + MSM yetSafety & efficacy in long-term use untested | Early-phase RCTs testing combined NAC + MSM vs. single agentsEndpoints: proinsulin/insulin ratio, insulin disulfide bond integrity, mitochondrial ATP |
Akt: protein kinase B; ATP: adenosine triphosphate; CBS: cystathionine β-synthase; ER: endoplasmic reticulum; GLUT4: glucose transporter type 4; GSH: glutathione; IL-6: interleukin-6; IRS-1: insulin receptor substrate-1; JNK: c-Jun N-terminal kinase; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LPS: lipopolysaccharide; MSM: methylsulfonylmethane; NAC: N-acetylcysteine; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PDI: protein disulfide isomerase; PI3K: phosphoinositide 3-kinase; T2DM: type 2 diabetes mellitus; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; HbA1c: hemoglobin A1c.
During the preparation of this work, the author(s) used ChatGPT (OpenAI) and Midjourney for figure design and language editing. The figures were generated by providing specific biochemical and structural data to these tools, and all outputs were subsequently reviewed, edited, and verified by the authors, who take full responsibility for the content of this publication.
MMA: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing—original draft, Writing—review & editing. AA: Supervision. Both authors read and approved the submitted version.
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