# Coverage and boundaries of the hypothesis collection

Reviewed 13 September 2026. [Index](README.md) · [Probability method](probability_method.md).

## Scope of the search

This is a broad, mechanism-oriented literature assessment of **diabetes-related structural injury or failed replacement of human peptidergic C-fiber terminals**. Other neuropathies serve as calibration examples. It includes 45 causal propositions, not 45 mutually exclusive etiologies or a census of every molecular regulator.

The assessment combined the preceding fatty-acid analysis, the repository's topic histories and source corrections, and searches of primary papers indexed through PubMed/PMC and journal sites. Search families combined diabetes/diabetic neuropathy with a mechanism or alias and with sensory neuron, DRG, Schwann cell, axon, skin denervation or intraepidermal fiber density. Follow-up searches checked human evidence, structural endpoints, intervention results and retractions where relevant. Searches were expanded when a separate initiating exposure appeared, as with amylin aggregation.

This was not a database-complete systematic review with a screened denominator. A family absent here has not been proved absent from the literature. The retrieved primary studies support the coverage stated below; a paper mentioning a pathway is not automatically evidence that it damages this fiber class. No claim is made that every citation was available in full text. Local public-data reanalyses are identified as such.

## What is grouped together

A separate file is useful when the hypothesis introduces a different exposure, necessary compartment transfer, limiting function, execution mechanism or loss-versus-replacement explanation. Several proteins governing the same causal requirement remain branches inside that file. A file can be broader than one experimentally resolved molecular pathway; its probability then prices that broader union.

| Literature term or related family | Where it belongs | Distinction retained |
|---|---|---|
| Aldose reductase, sorbitol, SORD, myo-inositol, polyol-associated redox changes | [01](01_polyol_flux.md) | Elevated flux, poor disposal and a toxic consequence are separate claims |
| Glucosamine, hexosamine biosynthesis, O-GlcNAc | [02](02_glucosamine_hexosamine.md) | O-GlcNAc is an optional mediator, not assumed from glucosamine toxicity |
| Glycated matrix/laminin/collagen, AGE receptors, reactive carbonyls | [03](03_extracellular_matrix_glycation.md), [04](04_rage_signaling.md), [05](05_methylglyoxal_carbonyl_stress.md) | Matrix effects, receptor signaling and direct chemical injury can differ |
| Glucose oxidation, respiratory reserve, AMPK/PGC-1, NAD balance | [06](06_glucose_mitochondrial_overload.md), [07](07_bioenergetic_insufficiency.md), [27](27_sarm1_axon_destruction.md), [28](28_parp_nad_depletion.md) | A narrow overload model is distinct from energy shortage and specific NAD-consuming executors |
| Palmitate, oleate, acylcarnitines, lipid droplets, oxidized LDL | [08](08_fatty_acid_delivery.md), [09](09_oxidized_ldl.md), [17](17_schwann_metabolic_support.md) | Mixture, unbound exposure and neuronal versus glial routing matter |
| Serine/alanine balance, PHGDH, SPT, deoxysphingolipids | [10](10_serine_deoxysphingolipids.md) | Human inherited toxicity supports capability, not the diabetic exposure bridge |
| Canonical ceramide species, sphingolipid balance, beneficial fatty-acid products | [11](11_canonical_ceramides.md), [43](43_protective_lipid_deficiency.md) | Toxic accumulation differs from a limiting protective product |
| Insulin/IGF, C-peptide, NGF/TrkA, PTEN and muscarinic growth control | [12](12_insulin_igf_trophic_deficit.md), [13](13_c_peptide_deficiency.md), [14](14_ngf_trophic_support.md), [44](44_intrinsic_growth_restriction.md) | Deficiency, resistance, adult dependence and growth restraint differ |
| Capillary dysfunction, hypoxia, nitric-oxide availability, DAG/PKC, nerve-barrier changes | [15](15_microvascular_ischemia.md), [16](16_pkc_vascular_signaling.md) | Structural vessel abnormalities need a consequential delivery deficit |
| Remak-cell support, Schwann mitochondrial/lipid metabolism, satellite glia, organelle transfer | [17](17_schwann_metabolic_support.md), [18](18_satellite_glial_mitochondrial_transfer.md) | C-fibers are unmyelinated; supportive glia still matter |
| TNF/TLR/NF-kappaB, inflammatory cytokines, protective macrophages, complement | [19](19_tnf_tlr4_inflammation.md), [20](20_loss_of_protective_macrophages.md), [22](22_complement_microvascular_injury.md) | Immune activation has no universal harmful sign |
| NLRP3, gasdermin, TBK1-associated pyroptosis | [21](21_inflammasome_pyroptosis.md) | Inflammasome signaling and actual lytic peripheral injury are different |
| UPR/CHOP, integrated stress signaling, proteostasis, autophagy/lysosomes, mitophagy | [23](23_er_stress.md), [24](24_autophagy_mitophagy.md) | Adaptive stress responses and static markers do not establish harmful flux |
| DRP1/MFN/OPA1, mitochondrial fragmentation, transport, HDAC6/tubulin | [25](25_mitochondrial_dynamics.md), [26](26_axonal_transport.md) | Morphology or motion must change useful local maintenance |
| SARM1/NMNAT2, PARP, GPX4/iron-dependent lipid injury, caspase-associated soma death | [27](27_sarm1_axon_destruction.md)–[30](30_neuronal_soma_apoptosis.md) | These are different execution or compartment claims, not interchangeable death markers |
| Sodium/calcium channels, calcium handling, ion-pump demand | [31](31_hyperexcitability_calcium.md) | Excess excitability must cross a structural injury threshold |
| Keratinocytes, terminal niche, repair factors, senescence/SASP | [32](32_skin_repair_environment.md), [33](33_senescence_sasp.md) | Failed replacement may lower density without increased destruction |
| Microbiome, endotoxin, short-chain fatty acids and other microbial products | [34](34_microbiome_metabolites.md) | Transferable community effects do not identify one mediator |
| Treatment-induced neuropathy, rapid HbA1c reduction, severe lows, glucose variability | [35](35_rapid_glycemic_correction.md), [41](41_hypoglycemic_energy_failure.md), [42](42_glycemic_variability.md) | Rate of improvement, absolute fuel deprivation and waveform shape differ |
| Nerve swelling, entrapment, repetitive mechanical stress | [36](36_mechanical_compression.md) | A focal lesion is not automatically the cause of symmetric distal DPN |
| Metformin-associated B12 deficiency, renal failure/uremic exposure | [37](37_metformin_b12_deficiency.md), [38](38_kidney_failure_uremic_exposure.md) | These use explicit treatment/comorbidity populations |
| ROS/RNS, peroxynitrite, antioxidant buffering | [39](39_oxidative_nitrosative_injury.md) | Damaging chemistry does not require one mitochondrial source |
| Metabolic memory, chromatin persistence, lasting exposure effects | [40](40_epigenetic_memory.md) | Persistent causal regulation differs from irreversible old damage |
| hIAPP/amylin oligomers and amyloid-related peptide toxicity | [45](45_amylin_aggregation.md) | Harmful aggregation differs from normal peptide signaling |

Aliases in this table locate a family. They do not confer a separately assessed probability on every named protein, lipid or process.

## Evidence deliberately kept outside a direct C-fiber claim

**Myelin-specific injury.** The MLKL diabetic-mouse study has strong manipulations of myelin decompaction and conduction. Its S441-linked myelin function is distinguished from canonical RIP3-dependent necroptotic phosphorylation. It cannot be copied directly into a claim that unmyelinated C-fibers die by necroptosis. A Remak-cell/support consequence would need the bridge in hypothesis 17; a distinct C-fiber necroptosis price is not justified by that myelin experiment. [Primary study](https://pmc.ncbi.nlm.nih.gov/articles/PMC9168919/).

**CNS and pain-only mechanisms.** Spinal microglial activation, central sensitization or altered withdrawal behavior can change pain without preserving a peripheral axon. Conversely, a central intervention could conceivably influence peripheral maintenance; that return path must be demonstrated rather than assumed. The TBK1 study's central knockdown and systemic treatment had different structural results, as discussed in [21](21_inflammasome_pyroptosis.md). The reported diabetes-associated dimethylglyoxal study concerns blood-brain barrier/cognitive outcomes; it does not supply a separate peripheral-fiber cause here. [Primary CNS study](https://www.nature.com/articles/s41467-024-50089-3).

**New cell-death labels or regulator lists.** A ferroptosis file is included because that specific injury claim has a retrievable experimental nerve literature, but it receives a low price for the human bridge. Cuproptosis, disulfidptosis and a broad “necroptosis” label are not assigned separate human C-fiber probabilities merely from review terminology or marker enrichment. This is a limitation of the assessed evidence, not a declaration that these processes cannot occur. Likewise, miRNAs, lncRNAs and individual kinase targets are grouped by the function their manipulation is proposed to change.

**Other causes of neuropathy.** Alcohol, chemotherapy, infections, autoimmune disease, inherited neuropathies and nutritional deficiencies unrelated to diabetes are not added as extra diabetes mechanisms. When they establish a useful causal capability, that narrower inference is stated locally. Foot-ulcer trauma is also not treated as an explanation of the earlier transition to incident DPN.

## Calibration examples and the inference they buy

| Example | Useful inference | Remaining gap |
|---|---|---|
| SORD-associated inherited axonal neuropathy | Severe polyol-disposal failure can injure human nerves | Ordinary diabetic exposure; predominantly motor inherited phenotype |
| HSAN1/deoxysphingolipid disease | The lipid chemistry can damage human sensory nerves | Concentration, duration and prevalence in type 2 diabetes |
| Human sensory-neuron SARM1 perturbation under other injuries | Human axons possess the execution route | Activation during diabetes and mature fiber subtype |
| Amyloid polyneuropathy and precursor suppression | A circulating amyloid precursor can causally affect human neuropathy | Amylin is a different precursor with a different local exposure |
| Nondiabetic advanced CKD with skin denervation | A renal-disease state can accompany human small-fiber loss independently of diabetes | Which exposure is causal and how much it contributes in diabetic CKD |
| Human randomized DPN intervention results | Challenge an unqualified culture/animal-to-human efficacy inference | A drug trial may not test the exact mediator, stage or structural endpoint |

These are selected anchors, not a denominator from which an empirical animal-to-human success rate can be computed. Primary citations and sample-size qualifications are in the linked mechanism files and the [method](probability_method.md).

## Where this leaves the original question

The collection identifies many physically plausible routes and makes their weak links explicit. It does not identify a uniquely proven cause in an individually typed human peptidergic neuron. The strongest confidence often concerns a general capability—energy failure, oxidative injury or axon execution—while the largest uncertainty concerns whether a specific diabetic exposure engages that capability, at the right place and time, enough to account for material human loss.

That separation is the intended use of the prices: decide which missing human bridge carries the uncertainty, rather than mistake a long molecular pathway or an attractive rescue for a completed causal explanation.