{
  "id": "08",
  "title": "Fatty-acid delivery",
  "summary": "Excess fatty-acid delivery may depolarize neuronal mitochondria and contribute to terminal loss.",
  "source_title": "Fatty-acid delivery and neuronal mitochondrial depolarization",
  "page": "08_fatty_acid_delivery.html",
  "source_markdown": "sources/08_fatty_acid_delivery.md",
  "structured_data": "data/08_fatty_acid_delivery.json",
  "snapshot_date": "2026-09-14",
  "source_review_date": "2026-09-14",
  "scope_label": "Early type 2 diabetes",
  "scope_exception": false,
  "source_headline_markdown": "**Best judgment: about 10%; coordinated sensitivity scenarios: 0.4–56%.** The explicit conditional product is 12.4%, which does not justify distinguishing this assessment sharply from 10% or 15%. These are subjective probabilities of the complete human proposition, not effect sizes or statistical confidence limits. Reviewed 14 September 2026. [Probability method](probability_method.md) · [Collection index](README.md).",
  "probability_percent": {
    "skeptical": 0.4134375,
    "base": 12.4215,
    "favorable": 55.7685
  },
  "probability_meaning": "Subjective belief in the complete causal proposition. Scenario endpoints are sensitivity products, not confidence limits.",
  "causal_proposition_markdown": "In adults diagnosed with type 2 diabetes within five years and without clinical DPN, persistently increased entry of **palmitate (16:0), stearate (18:0), or both** into peptidergic sensory neurons lowers mitochondrial membrane potential. Preventing that input-dependent depolarization before injury would reduce five-year net skin-terminal loss by at least 20%, in a baseline-describable group accounting for at least 10% of reference-care incident DPN cases.\n\nThis assessment concerns a specified mitochondrial branch of direct neuronal fatty-acid injury. The broader proposition that some lipid disturbance damages peripheral nerves includes additional exposures and mechanisms. Injury confined to Schwann cells, vascular lipid effects, extracellular lipid-receptor signaling, deoxysphingolipids supplied from elsewhere, and mitochondrial injury without this depolarization mechanism do not establish the complete claim here. Palmitate and stearate are named because they have direct sensory-neuron perturbation evidence; no assumption is made that all saturated fatty acids share their effects.\n\nThe relevant compartments are the sensory neuron's DRG soma, peripheral axon and skin terminal, with biochemical measurements connected to the same neurons whose terminals are followed. Increased delivery means a greater **molar inward entry rate** of either named nonesterified fatty acid across the neuronal membrane, not a higher blood triglyceride concentration, total tissue lipid content or neuronal lipid released from internal stores. Lipoprotein lipolysis can contribute to the extracellular supply, but the initiating species crossing the neuron membrane must be identified. Increased entry can coexist with increased export and no net lipid accumulation.\n\nAllowed baseline groups are the whole eligible population, fasting triglycerides≥150 mg/dL, HbA1c≥7.5%, or neuronal palmitate/stearate entry above the matched nondiabetic 95th percentile. Membership cannot depend on later decline or response. R1 requires a permitted group's mean entry rate for at least one named species above its age-, sex- and ordinary-activity-matched nondiabetic 95th percentile for≥90 cumulative days during year one, while relevant structures remain intact before losses attributed to this route. All baseline participants and early losses remain in the assessment. The species, group and connected neuronal compartments must agree throughout the chain.\n\nFor each person, five-year net loss L equals terminal disappearances minus newly established terminals, divided by baseline terminal count. Track actual structures and stable peptidergic identity, not altered peptide staining. New terminals that subsequently disappear enter both counts. For positive reference-care mean loss L0 and intervention mean loss L1, define B=(L0−L1)/L0. A smaller structural contribution means B≥0.05; materiality means B≥0.20. Coverage C is the share of all **reference-care incident cases** in the qualifying group and must be≥0.10. Incident DPN requires new bilateral length-dependent sensory signs with objective small-fiber loss or abnormal nerve conduction, excluding another neuropathy cause. These are chosen truth boundaries, not observed constants.",
  "claims": [
    {
      "id": "R1",
      "source_id": "R1",
      "claim": "Palmitate/stearate inward entry has the specified persistent pre-loss elevation.",
      "claim_markdown": "Palmitate/stearate inward entry has the specified persistent pre-loss elevation.",
      "conditional_percent": {
        "skeptical": 45.0,
        "base": 70.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 70.0,
      "source_cumulative_display": "70%",
      "reason_markdown": null,
      "question": "Is entry of palmitate, stearate, or both into sensory neurons persistently elevated before terminal loss?"
    },
    {
      "id": "R2",
      "source_id": "R2",
      "claim": "Normalizing that entry with F increases neuronal mitochondrial Ψ during the exposure periods.",
      "claim_markdown": "Normalizing that entry with F increases neuronal mitochondrial Ψ during the exposure periods.",
      "conditional_percent": {
        "skeptical": 30.0,
        "base": 65.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 45.5,
      "source_cumulative_display": "45.5%",
      "reason_markdown": null,
      "question": "Would normalizing palmitate or stearate entry increase the electrical potential across neuronal mitochondrial inner membranes?"
    },
    {
      "id": "R3",
      "source_id": "R3",
      "claim": "Preventing that input-dependent depolarization with P reduces five-year net terminal loss by≥5%.",
      "claim_markdown": "Preventing that input-dependent depolarization with P reduces five-year net terminal loss by≥5%.",
      "conditional_percent": {
        "skeptical": 25.0,
        "base": 60.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 27.3,
      "source_cumulative_display": "27.3%",
      "reason_markdown": null,
      "question": "Would selectively preventing the mitochondrial depolarization caused by excess palmitate or stearate entry avert at least 5% of five-year net terminal loss?"
    },
    {
      "id": "R4",
      "source_id": "R4",
      "claim": "The same P benefit reaches≥20%.",
      "claim_markdown": "The same P benefit reaches≥20%.",
      "conditional_percent": {
        "skeptical": 35.0,
        "base": 65.0,
        "favorable": 85.0
      },
      "cumulative_base_percent": 17.745,
      "source_cumulative_display": "17.75%",
      "reason_markdown": null,
      "question": "Would preventing the mitochondrial depolarization caused by excess palmitate or stearate entry avert at least 20% of five-year net terminal loss?"
    },
    {
      "id": "R5",
      "source_id": "R5",
      "claim": "A group satisfying R1–R4 contains≥10% of reference-care incident DPN cases.",
      "claim_markdown": "A group satisfying R1–R4 contains≥10% of reference-care incident DPN cases.",
      "conditional_percent": {
        "skeptical": 35.0,
        "base": 70.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 12.4215,
      "source_cumulative_display": "12.42%",
      "reason_markdown": null,
      "question": "Does the benefiting subgroup account for at least 10% of incident DPN cases under reference care?"
    }
  ],
  "sections": [
    {
      "heading": "The causal proposition",
      "markdown": "In adults diagnosed with type 2 diabetes within five years and without clinical DPN, persistently increased entry of **palmitate (16:0), stearate (18:0), or both** into peptidergic sensory neurons lowers mitochondrial membrane potential. Preventing that input-dependent depolarization before injury would reduce five-year net skin-terminal loss by at least 20%, in a baseline-describable group accounting for at least 10% of reference-care incident DPN cases.\n\nThis assessment concerns a specified mitochondrial branch of direct neuronal fatty-acid injury. The broader proposition that some lipid disturbance damages peripheral nerves includes additional exposures and mechanisms. Injury confined to Schwann cells, vascular lipid effects, extracellular lipid-receptor signaling, deoxysphingolipids supplied from elsewhere, and mitochondrial injury without this depolarization mechanism do not establish the complete claim here. Palmitate and stearate are named because they have direct sensory-neuron perturbation evidence; no assumption is made that all saturated fatty acids share their effects.\n\nThe relevant compartments are the sensory neuron's DRG soma, peripheral axon and skin terminal, with biochemical measurements connected to the same neurons whose terminals are followed. Increased delivery means a greater **molar inward entry rate** of either named nonesterified fatty acid across the neuronal membrane, not a higher blood triglyceride concentration, total tissue lipid content or neuronal lipid released from internal stores. Lipoprotein lipolysis can contribute to the extracellular supply, but the initiating species crossing the neuron membrane must be identified. Increased entry can coexist with increased export and no net lipid accumulation.\n\nAllowed baseline groups are the whole eligible population, fasting triglycerides≥150 mg/dL, HbA1c≥7.5%, or neuronal palmitate/stearate entry above the matched nondiabetic 95th percentile. Membership cannot depend on later decline or response. R1 requires a permitted group's mean entry rate for at least one named species above its age-, sex- and ordinary-activity-matched nondiabetic 95th percentile for≥90 cumulative days during year one, while relevant structures remain intact before losses attributed to this route. All baseline participants and early losses remain in the assessment. The species, group and connected neuronal compartments must agree throughout the chain.\n\nFor each person, five-year net loss L equals terminal disappearances minus newly established terminals, divided by baseline terminal count. Track actual structures and stable peptidergic identity, not altered peptide staining. New terminals that subsequently disappear enter both counts. For positive reference-care mean loss L0 and intervention mean loss L1, define B=(L0−L1)/L0. A smaller structural contribution means B≥0.05; materiality means B≥0.20. Coverage C is the share of all **reference-care incident cases** in the qualifying group and must be≥0.10. Incident DPN requires new bilateral length-dependent sensory signs with objective small-fiber loss or abnormal nerve conduction, excluding another neuropathy cause. These are chosen truth boundaries, not observed constants."
    },
    {
      "heading": "From delivered fat to a mitochondrial consequence",
      "markdown": "Albumin-bound and unbound fatty acids exchange. Binding controls the available monomer concentration, but uptake also depends on dissociation, local replenishment, membrane transport and intracellular trapping. Neither total concentration nor a single unbound measurement alone gives neuronal flux. Palmitate arriving at the neuron can be oxidized, esterified into membrane lipids, desaturated, stored in neutral droplets or exported. A change in a particular ceramide or triglyceride pool is therefore not compulsory. Buffering can prevent an effect despite elevated entry.\n\nThe exposure branches are palmitate alone, stearate alone, or both. The joint branch requires both persistent elevations; a branch must retain its identity throughout. Let F be an ideal adult-onset, neuron-restricted normalization of inward entry of exactly that branch to its matched nondiabetic trajectory. It acts on entry itself, preserving extracellular fatty-acid concentrations and receptor occupancy, other fatty-acid inputs, systemic glycemia, oxygen delivery, trophic support and glial exposure. Reduced neuronal uptake must not simply divert the excess into adjacent support cells. Exported or diverted material is accounted for. Intracellular lipid handling and subsequent signaling may respond. A statin, dietary substitution or complete CD36 deletion is not F.\n\nLet Ψ be the magnitude of the matrix-negative electrical potential across the mitochondrial inner membrane, measured in millivolts with calibration for probe uptake, pH and organelle volume. **Depolarization here means that Ψ is lower under reference entry than under F.** It is defined by that biochemical contrast without assuming that the difference is damaging. R2 requires a strictly positive mean Ψ difference, F minus reference, during the R1 exposure periods. There is no arbitrary minimum millivolt difference: the later structural rows supply the consequential-effect threshold.\n\nLet P be an ideal mitochondrial voltage controller that reproduces the Ψ trajectory generated by F while retaining reference fatty-acid entry. It supplies explicitly accounted external energy and charge transfer, maintaining matrix/intermembrane-space pH at their reference trajectories to distinguish the electrical component from a separate pH intervention. It does not directly scavenge oxidants, inhibit apoptosis, move organelles or supply cytosolic ATP. ATP synthesis, calcium handling, oxidant production, organelle transport and downstream repair may change because the electrical potential changes. A defined field/charge adjustment with feedback is the idealization; an unspecified switch that restores mitochondrial health is not.\n\nLower Ψ can be injurious, compensated, or protective. Mild depolarization may reduce electron leak; maintaining a higher potential can increase oxidant production or calcium uptake. Greater ATP-linked respiration need not mean greater reserve, and less mitochondrial motion need not mean deficient local support. Accordingly, neither transport arrest, ATP depletion nor apoptosis is a necessary additional row. P's net structural consequence determines whether the input-dependent voltage change matters."
    },
    {
      "heading": "Probability decomposition",
      "markdown": "Every conditional after R1 assumes all predecessors in the **same** permitted group, implicated fatty-acid input and connected neurons. At each stage retain only groups meeting every earlier requirement. No independence assumption is used, and the conjunction includes structural magnitude and case coverage.\n\n| Claim | Additional proposition | Skeptical / best / favorable | Cumulative best |\n|---|---|---:|---:|\n| R1 | Palmitate/stearate inward entry has the specified persistent pre-loss elevation. |45 / **70** /90%|70%|\n| R2 | Normalizing that entry with F increases neuronal mitochondrial Ψ during the exposure periods. |30 / **65** /90%|45.5%|\n| R3 | Preventing that input-dependent depolarization with P reduces five-year net terminal loss by≥5%. |25 / **60** /90%|27.3%|\n| R4 | The same P benefit reaches≥20%. |35 / **65** /85%|17.75%|\n| R5 | A group satisfying R1–R4 contains≥10% of reference-care incident DPN cases. |35 / **70** /90%|12.42%|\n\nR1 is plausible given common dyslipidemia, but human neuronal entry has not been measured. R2 has direct culture support plus an in vivo dietary association with potential, tempered by dose, mixture and species differences. R3 remains uncertain even after accepting depolarization: preserving voltage may fail to repair another limiting process or increase a competing injury. R4 prices magnitude after accepting a small effect. R5 prices commonness, which neither severe culture exposure nor one susceptible mouse strain determines. The ranges express materially different interpretations of these gaps, not estimates derived by counting papers."
    },
    {
      "heading": "Evidence that constrains the claim",
      "markdown": "**Direct sensory-neuron exposure supports the biochemical possibility.** In adult mouse DRG cultures, 31.25 µM palmitate did not impair mitochondrial motility, whereas 62.5–250 µM did; 125–250 µM nearly abolished movement by 24 h. The control medium contained 6.1 mM glucose, and palmitate was prepared with 0.25% fatty-acid-free BSA. That is approximately 37.6 µM albumin, giving palmitate:albumin ratios 0.83–6.65 across the doses. The depolarization analysis averaged 51 neurons across 3–5 experimental replicates; those neurons are not 51 independent animals. Respiratory assays pooled neurons from two mice per plate. Palmitate increased basal respiration/ATP turnover while impairing coupling, illustrating why depolarization cannot simply be relabeled ATP depletion. Culture glucose challenges did not reproduce the transport arrest. [Rumora et al., 2018](https://pmc.ncbi.nlm.nih.gov/articles/PMC6191072/).\n\nThe chain-length experiment found transport/potential/ATP and apoptotic abnormalities with palmitate or stearate, but not the same pattern with 31.25–250 µM laurate or myristate. Partial recovery after a12 h washout did not establish irreversible damage. These were short culture perturbations, not longitudinal terminal counts or a measured human lipid mixture. The accessible summaries do not recover an animal-level n for every panel. [Rumora et al., 2019, chain-length study](https://pmc.ncbi.nlm.nih.gov/articles/PMC6314260/).\n\n**Mixture matters, and lipid droplets are not yet the necessary mediator.** Oleate preserved transport and potential under palmitate exposure. The potential panel counted 31–35 neurons/condition; ATP/apoptosis assays used the 50B11 sensory cell line, not the same adult primary neurons. Lipid droplets appeared most clearly at 250 µM oleate, although lower oleate concentrations could protect transport, leaving other mechanisms open. In the associated diet study, changing lard-based 60%-fat chow to high-oleic sunflower-oil 60%-fat chow at 16 weeks improved nerve conduction and skin innervation by 24 weeks. Groups were 5 standard-diet, 7 HFD and 8 switched mice. Weight/glucose intolerance persisted. This is a structural animal positive, but dietary substitution changes many cells and signals rather than selectively restoring neuronal Ψ. “No significant difference from controls” does not demonstrate exact complete recovery. [Rumora et al., 2019, dietary and mixture study](https://pmc.ncbi.nlm.nih.gov/articles/PMC6510336/).\n\n**Nominal culture dose does not establish human free dose.** In pooled reference plasma from 100 healthy donors, Huber and Kleinfeld measured 1.6 nM total unbound fatty acid against 208 µM total nonesterified fatty acid. The unbound palmitate fraction was 0.114, approximately 0.18 nM; stearate was approximately 0.12 nM. Repeated measurements of that pool are not 100 independent exposure profiles. This establishes the distinction between bound and unbound chemistry, not the concentration surrounding diabetic axons. Comparing 250 µM total culture palmitate directly with 0.18 nM unbound plasma palmitate would also be wrong: unbound culture exposure was not measured. [Huber and Kleinfeld, 2017](https://pmc.ncbi.nlm.nih.gov/articles/PMC5335587/).\n\n**The in vivo mitochondrial comparison partly contradicts culture.** HFD-fed mice had altered axonal potential and stimulus responses, but no general transport arrest in electrically active myelinated saphenous axons. The transport comparisons used 2–3 mice/group, despite dozens of measured axons. Some motile-number or velocity measures increased. This supports mitochondrial disturbance under dietary stress while challenging a compulsory transport-failure sequence; it supplies neither selective fatty-acid entry nor peptidergic terminal survival. [Sajic et al., 2021, primary manuscript](https://discovery.ucl.ac.uk/10125876/1/JNEUROSCI.1852-20.2021.full.pdf).\n\n**Dietary structural rescue is variable.** A2026 study allocated 10 mice/arm to standard, saturated-fat HFD, monounsaturated-fat HFD, or a switch at 18 weeks. Conduction recovered after the switch. Its terminal skin panel displays only three points/arm: approximate means 61, 46, 57 and 51 in the printed mm⁻² units. The switch-minus-HFD contrast is about+4.8. Treating the three points as independent gives an illustrative unadjusted 95% interval−10.0 to 19.6; the subset's independent unit is not explained. This is not precise structural replication, and the printed unit differs from standard fibers/mm. Altered nerve cytokines provide an alternative to an exclusively neuronal mechanism. [Scott et al., 2026](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1769812/full).\n\nIn obese rats, replacing half the lard-derived fat with olive oil for 32 weeks after 16 weeks of HFD supplied little benefit compared with the larger response to menhaden oil. The relevant groups had 11 HFD, 9 olive-oil and 9 menhaden-oil rats. Circulating total free fatty acids were 0.48±0.09, 0.42±0.05 and 0.32±0.05 mM respectively, SEM. Neither a nonspecific positive nor a formulation-dependent negative isolates P. [Coppey et al., 2018](https://pmc.ncbi.nlm.nih.gov/articles/PMC5898889/).\n\n**Fat can also support neuronal function.** Independent 2025 perturbation studies showed that neurons can mobilize stored triglycerides through DDHD2 and use fatty acids for mitochondrial ATP generation. These concern brain neurons and a different source of fatty acids, rather than excessive extracellular delivery in DPN. They defeat the assumption that neuronal saturated-fatty-acid flux is intrinsically wasteful or invariably toxic; normalizing excess entry must preserve useful fuel and membrane supply. [Kumar et al., 2025](https://doi.org/10.1038/s42255-025-01321-x); [Saber et al., 2025](https://doi.org/10.1038/s42255-025-01367-x).\n\n**Human structure and temporal association are supportive but modest.** Among 427 people with established DPN and paired 52-week sural biopsies, triglycerides correlated with myelinated-fiber-density change at r=−0.110, approximately 1.2% shared variance; the reconstructed unadjusted correlation interval is−0.203 to−0.015. The matched progression comparison used 104 versus 104 participants, not a separate cohort. The sample was 78% T2, with mean diabetes duration 12.3 years. It does not establish early C-fiber exposure or mitochondrial mediation. [Wiggin et al., 2009](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699859/).\n\nIn69 Pima participants, 27 later met the neuropathy threshold and 42 did not. Serum had been banked approximately 10 years earlier; baseline neuropathy exclusion was not documented, and tabulated diabetes duration was about 15.5 years. Total free-fatty-acid abundance differed at nominal p=.042 across a435-lipid/18-class analysis, with no reported correction across the class family and backward covariate selection. Blood pressure and albuminuria differed. Lipid peak abundance is not unbound concentration or nerve flux, and the study's favorable language about incident disease cannot replace a baseline examination. [Afshinnia et al., 2022](https://pmc.ncbi.nlm.nih.gov/articles/PMC9463947/).\n\nAnother cross-sectional study compared 49 T2 participants without DPN, 48 with DPN and 9 lean controls. The diabetic groups averaged about 12 years' duration; the marked obesity difference from lean controls complicates diabetes contrasts. Its reported classifier AUROC0.88 used eight selected metabolites spanning several pathways, including xenobiotics, and does not identify palmitate delivery or a mitochondrial cause. [Rumora et al., 2021](https://pmc.ncbi.nlm.nih.gov/articles/PMC8164865/).\n\n**Human lipid treatment and genetics do not settle the route.** Fremantle's531-person longitudinal subgroup gave observational neuropathy hazard ratios 0.52(0.27–0.98) for fibrate use and 0.65(0.46–0.93) for statins. A much larger Danish study of 259, 625 people with incident T2 found adjusted statin hazard ratios 1.05(0.98–1.11) for new users and 0.97(0.91–1.04) for prevalent users. These measure clinical neuropathy, with nonrandom treatment and no neuronal entry/voltage engagement; statin neutrality is not a selective fatty-acid-delivery null. [Davis et al., 2008](https://pubmed.ncbi.nlm.nih.gov/18193189/); [Kristensen et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32998990/).\n\nA179-lipid Mendelian-randomization study reported two phosphatidylcholine associations after false-discovery correction, using relaxed exposure-variant selection and FinnGen's broad DM_NEUROPATHY outcome. Neither phosphatidylcholine species is unbound palmitate/stearate delivery to neurons; these results provide no genetic estimate of F or P. [Wang et al., 2025](https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1398691/full). No retrieved human selective perturbation establishes the complete early-prevention comparison."
    },
    {
      "heading": "Ideal experiments that would resolve each claim",
      "markdown": "These are ideal truth conditions, not proposed studies. They require repeated noninjurious measurements of human neuronal lipid entry, calibrated mitochondrial voltage and identified peptidergic terminals, plus selective adult intervention. Use a representative early-T2 population and matched nondiabetic references. People are the independent units. Define groups before outcome observation. All causal arms retain the same diabetes care, extracellular lipid-receptor exposure, other fatty-acid entry, oxygen, glycemia, trophic input and initiating inflammation. Downstream responses may change. Simultaneous intervals must account for the finite subgroup/species comparisons; a boundary-spanning result remains unresolved.\n\n**R1 — persistent pre-loss entry.** With no predecessors assumed, measure inward palmitate and stearate flux using isotope-resolved, concentration-calibrated transport measurements during ordinary feeding, fasting, sleep and activity from baseline through year one. Separate entry from export, local synthesis and internal lipolysis; measure unbound interstitial species and albumin exchange to interpret the flux. Link soma/axon observations to the terminals followed for five years. YES requires at least one allowed group/species to meet the 95th-percentile and 90-day definition before the losses attributed to it. NO requires that no allowed group/species meets it with adequate sampling and precision. Missing high-demand periods, only plasma chemistry, uncalibrated tracer enrichment, or selection of survivors is unresolved. Human serum associations and cultured nominal doses do not resolve this measurement.\n\n**R2 — input-dependent depolarization.** Assuming R1 in the same group and neuronal compartments, randomize F versus sham and measure Ψ during the specified exposure periods. Verify the inward-flux normalization while preserving other initiating inputs and accounting for diverted material. Reversible restoration of the original entry trajectory tests whether the voltage response follows the named input. YES is a strictly positive group-mean Ψ contrast, F minus reference; NO is a nonpositive contrast for every qualifying species branch. An interval wholly above zero establishes YES and one wholly below zero NO. Exact zero belongs to NO but ordinarily remains unresolved by finite measurement. A fluorescent intensity change without calibrated voltage, or potential measured only after fragmentation, does not decide this row. Existing culture contrasts support possibility; the natural human entry/voltage contrast is missing.\n\n**R3 — a smaller structural consequence of that voltage change.** Assuming R1–R2, randomize P versus a matched sham from entry through five years. Calibrate its voltage target from the F comparison under the same ordinary activity states, applying it only to the input-dependent voltage change. Confirm reference fatty-acid entry and reference matrix/intermembrane-space pH; quantify the external energy/charge needed to maintain Ψ. ATP generation, calcium and oxidants may respond to Ψ, but P must not directly alter those processes through a second mechanism. An independent voltage-control method and restoration of the original voltage trajectory check specificity. Count actual terminal disappearances and entries. YES is B≥0.05; NO is B<0.05, with an interval wholly on the relevant side. For example, L0=.30 and L1=.28 gives B=.067 and meets this row without meeting R4. Failed voltage engagement, extra direct pharmacology, pain-only improvement or insufficient structural precision is unresolved. Current dietary and oleate interventions do not implement this selective voltage comparison.\n\n**R4 — material magnitude.** Assuming R1–R3, estimate the same P effect over five years in the same baseline group. YES requires B≥0.20; NO is B<0.20 at adequate precision. With L0=.30, L1=.24 lies on the truth boundary; .23 passes and .28 fails. Propagate uncertainty in the reference loss denominator. A true nonpositive L0 fails the specified relative-preservation proposition; a poorly estimated near-zero denominator remains unresolved. More mitochondria, restored conduction or normal-looking potential does not replace the net terminal-loss endpoint. No current human study supplies this magnitude for P.\n\n**R5 — incident-case coverage.** Assuming a group satisfies R1–R4, estimate C in a population-representative reference-care arm over the same five years, accounting for follow-up loss and competing death in the defined incident-case population. YES requires C≥0.10 for at least one otherwise qualifying group; NO requires C<0.10 for all of them at adequate precision. A group containing 3% of reference incident cases fails even with a large benefit; 15% qualifies. An enriched dyslipidemic trial alone, responder-defined groups or the fraction of cases remaining after treatment cannot establish C. Existing studies lack the paired neuronal classification and incident-case coverage."
    },
    {
      "heading": "Calibration and remaining uncertainty",
      "markdown": "The best inputs[70, 65, 60, 65, 70]% multiply to 12.4215%. The skeptical inputs[45, 30, 25, 35, 35]% give 0.4134%, assuming that human entry is buffered, the culture free dose is unusually high, and voltage correction leaves dominant damage routes active. Favorable inputs[90, 90, 90, 85, 90]% give 55.7685%, assuming that sustained entry and input-dependent depolarization are common and causally important before loss. These are coordinated sensitivity scenarios. Their approximately 55-percentage-point span measures uncertainty in interpretation; it is not a confidence interval or a probability distribution from which a variance can be inferred.\n\nThe consequential gaps are the natural human dose/flux and the structural effect of specifically preventing its voltage consequence. Hypothetically raising only R2 from 65% to 90% changes the complete probability to 17.2%; lowering it to 25% gives 4.8%. Real evidence joining exposure, voltage and structure would also update R3 and perhaps coverage. R1 and R2 can be merged into a45.5% joint condition without changing the headline. Adding optional intracellular pools, motors or ATP consumers must not create automatic extra discounts.\n\nShorter exposure requirements, a10% materiality threshold, or inclusion of non-depolarizing mitochondrial lipid routes would broaden the proposition; 30% materiality narrows it. Existing evidence cannot price a reliable threshold-response curve. The number here is not the probability that all dietary-fat manipulation fails, nor a ranking of particular diets or drugs. The [quantitative support](../../../findings/damage_calibration_fatty_acid_quantitative.md) gives the dose arithmetic and figure checks."
    },
    {
      "heading": "Relationship to other hypotheses",
      "markdown": "[ATP insufficiency](07_bioenergetic_insufficiency.md), [mitochondrial dynamics](25_mitochondrial_dynamics.md), [axonal transport](26_axonal_transport.md) and [oxidative injury](39_oxidative_nitrosative_injury.md) are possible consequences or alternative explanations. None is automatically implied by the specified voltage-mediated terminal effect: calcium or other voltage-dependent functions can mediate it. [Oxidized LDL](09_oxidized_ldl.md), [deoxysphingolipids](10_serine_deoxysphingolipids.md), [canonical ceramides](11_canonical_ceramides.md) and [protective lipids](43_protective_lipid_deficiency.md) are related, overlapping claims. Shared dietary experiments are one piece of evidence, not independent support each time they appear."
    }
  ],
  "source_claim_table_markdown": "| Claim | Additional proposition | Skeptical / best / favorable | Cumulative best |\n|---|---|---:|---:|\n| R1 | Palmitate/stearate inward entry has the specified persistent pre-loss elevation. |45 / **70** /90%|70%|\n| R2 | Normalizing that entry with F increases neuronal mitochondrial Ψ during the exposure periods. |30 / **65** /90%|45.5%|\n| R3 | Preventing that input-dependent depolarization with P reduces five-year net terminal loss by≥5%. |25 / **60** /90%|27.3%|\n| R4 | The same P benefit reaches≥20%. |35 / **65** /85%|17.75%|\n| R5 | A group satisfying R1–R4 contains≥10% of reference-care incident DPN cases. |35 / **70** /90%|12.42%|"
}