This comparative framework highlights the novel perspective of the Sulfur-Dependent Misfolding Hypothesis in redefining T2DM as a sulfur metabolism disorder, contrasting it with traditional paradigms.
| Comparative dimension | Traditional paradigm of T2DM | Sulfur-Dependent Misfolding Hypothesis |
|---|---|---|
| Root cause | Peripheral insulin resistance is driven by obesity, lipotoxicity, and inflammation. | Structural misfolding of insulin due to disulfide bond disruption caused by organic sulfur deficiency. |
| Initiation site | Skeletal muscle, liver, and adipose tissue. | Mitochondrial dysfunction in intestinal epithelial cells impairs sulfur metabolism. |
| Pathophysiological focus | Post-receptor signaling defects (IRS, PI3K, Akt). | Primary insulin deformation with reduced receptor affinity due to disrupted disulfide bonds. |
| Explanation of the hyperinsulinemia + hyperglycemia paradox | Compensatory hypersecretion due to peripheral resistance. | Endogenous insulin is misfolded and non-functional; exogenous insulin remains effective due to its intact structure. |
| Immunological mechanism | Chronic inflammation in adipose tissue and macrophage activation. | Glutathione depletion induces NF-κB and JNK pathways via oxidative stress and endotoxemia. |
| Role of the gut | Secondary influence via microbiome and inflammation. | Primary site of dysfunction initiating mitochondrial suffocation, impaired sulfur metabolism, and mucosal barrier breakdown. |
| Insulin signaling defect | Impaired receptor signaling due to inflammation and phosphorylation of IRS. | Insulin fails to initiate signaling due to misfolded structure with up to 70% loss in receptor affinity. |
| Therapeutic strategy | Blood glucose control via metformin, GLP-1 agonists, or exogenous insulin. | Sulfur restoration through NAC, MSM, and dietary methionine/cysteine to stabilize insulin structure. |
| Experimental accessibility | HOMA-IR index and indirect measures of resistance. | Direct structural assessment of insulin via LC-MS/MS and Raman spectroscopy. |
| Biochemical depth | Focuses downstream of the IR. | Traces the issue upstream to insulin biosynthesis and protein folding integrity. |
| Innovation potential | Incremental improvements to a saturated model. | A paradigm shift introducing sulfur metabolism as a central therapeutic and diagnostic axis. |
| Philosophical reframing | The body becomes resistant to insulin. | The body produces dysfunctional insulin; the issue lies at the source. |
Akt: protein kinase B; IR: insulin receptor; IRS: IR substrate; JNK: c-Jun N-terminal kinase; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MSM: methylsulfonylmethane; NAC: N-acetylcysteine; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphoinositide 3-kinase; T2DM: type 2 diabetes mellitus; HOMA-IR: homeostatic model assessment of insulin resistance.
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.
The authors declare that there are no conflicts of interest.
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