Coverage and boundaries of the hypothesis collection

Reviewed 14 September 2026. Index · Probability method.

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 and 210 conditional claims. The propositions overlap and do not constitute a census of every molecular regulator.

The assessment uses primary papers, public source data, trial records and the repository's scientific topic histories. Searches combine diabetes/diabetic neuropathy with a mechanism or alias and with sensory neuron, DRG, Schwann cell, axon, skin denervation or intraepidermal fiber density. Detailed checks address human dose, independent sample counts, structural outcomes, interventions, retractions and duplicated reports. The collection-wide review also checked shared evidence, the highest and lowest estimates, and every conditional table against its resolving comparisons.

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.

Operational scope

The main question is physical preservation in initially DPN-free early T2D. The files define their finite candidate groups, molecular alternatives, exposure thresholds and interventions. A negative result for one of these bounded questions does not reject every process sharing its name.

Seven notes have population or endpoint exceptions: 13 uses secretion-deficient T1D; 35 uses six-month injury after rapid correction; 37 uses prolonged metformin exposure; 38 uses advanced CKD; 40 uses sustained glycemic improvement; 41 uses substantial verified lows under any treatment; and 44 uses established-DPN repair. The new/progressive denominators in 37, 38, 40 and 41, and the population-coverage denominator in 44, are not early-T2 incident-case coverage.

The intervention definitions also matter. Hypothesis 08 prices the saturated-fatty-acid input to mitochondrial-voltage route, not every lipid effect. Hypothesis 20 prices dead-material clearance, not every macrophage benefit. Hypothesis 24 prices post-enclosure disposal completion, not all autophagy initiation. Hypothesis 39 uses a finite reactive-chemistry panel; 43 uses specified physiological lipid profiles with compositional displacement. Related routes outside those interventions remain unpriced.

Every note gives a best probability and scenario-sensitivity range for every row and the whole proposition. The index has the current numbers. Their breadth reflects missing measurements and uncertain transfer, rather than a fitted probability distribution.

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.

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.

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. 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.

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

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.

What this says about prevention

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.