Intranasal insulin
Open accessAbstract
The intranasal (IN) route enables the delivery of insulin to the central nervous system in the relative absence of systemic uptake and related peripheral side effects. Intranasally administered insulin is assumed to travel along olfactory and adjacent pathways and has been shown to rapidly accumulate in cerebrospinal fluid, indicating efficient transport to the brain. Two decades of studies in healthy humans and patients have demonstrated that IN insulin exerts functional effects on metabolism, such as reductions in food intake and body weight and improvements of glucose homeostasis, as well as cognition, ie, enhancements of memory performance both in healthy individuals and patients with mild cognitive impairment or Alzheimer's disease; these studies moreover indicate a favourable safety profile of the acute and repeated use of IN insulin. Emerging findings suggest that IN insulin also modulates neuroendocrine activity, sleep‐related mechanisms, sensory perception and mood. Some, but not all studies point to sex differences in the response to IN insulin that need to be further investigated along with the impact of age. “Brain insulin resistance” is an evolving concept that posits impairments in central nervous insulin signalling as a pathophysiological factor in metabolic and cognitive disorders such as obesity, type 2 diabetes and Alzheimer's disease, and, notably, a target of interventions that rely on IN insulin. Still, the negative outcomes of longer‐term IN insulin trials in individuals with obesity or Alzheimer's disease highlight the need for conceptual as well as methodological advances to translate the promising results of proof‐of‐concept experiments and pilot clinical trials into the successful clinical application of IN insulin.
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TL;DR
This narrative review summarizes two decades of human research on intranasal (IN) insulin as a non-invasive route for delivering insulin to the central nervous system, covering its metabolic, neuroendocrine, sleep, cognitive, sensory and mood effects. It concludes that IN insulin is a powerful experimental tool with a favourable safety profile, but that negative results from longer-term trials in obesity and Alzheimer's disease mean clinical application remains some way off.
Key findings
- IN insulin bypasses the blood-brain barrier and is detectable in cerebrospinal fluid within 1 hour of administration in healthy humans; it is assumed to travel along olfactory and adjacent pathways.
- Metabolic effects: 8 weeks of IN insulin (4 × 40 IU/day) reduced body weight and body fat in men but not women, with a 27% reduction in circulating leptin in the men; acute 160 IU reduced food intake in fasted men but not women; postprandial (not preprandial) administration reduced intake and rated palatability of chocolate cookies in women; pre-sleep 160 IU reduced breakfast intake in both sexes and across age groups, but 8 weeks of once-daily pre-sleep 160 IU did not reduce body weight in healthy men.
- Glucoregulatory effects: after 160 IU IN insulin, a higher glucose infusion rate was needed to maintain blood glucose in normal-weight participants (suggesting enhanced suppression of endogenous glucose production and increased peripheral glucose uptake), with hypothalamic and striatal involvement — effects not found in obese individuals; IN insulin suppressed endogenous glucose production only in normal-weight, not overweight/obese, participants.
- Cognitive effects: 8 weeks of IN insulin improved delayed recall of a 30-word list (hippocampus-dependent declarative memory) in young men and women, replicated in obese men; in MCI/AD, acute improvements were seen only in apoE ε4 non-carriers, and a 4-month trial found enhanced 20-minute story recall in the 20-IU but not 40-IU group, with preserved caregiver-rated functional ability and attenuated hypometabolism progression in both insulin groups.
- Safety: across 38 acute studies (doses 10–160 IU; 1092 participants) up to 2 November 2017, no adverse events or hypoglycaemia occurred; 18 chronic studies (daily 20–160 IU or 0.5–1.5 U/kg for 21 days to 9.7 years; 832 participants) reported the only symptomatic hypoglycaemia case after placebo spray. Nasal mucosa irritation is the most commonly reported side effect.
- The multisite phase 2/3 trial (27 sites, 289 participants aged 55–85 with amnestic MCI or AD) found no differences between insulin and placebo in the primary measure (ADAS-cog-12) or other clinical/CSF parameters; secondary analyses of the first-device subgroup showed improved ADAS-cog-12 in insulin (n = 23) vs placebo (n = 22).
- Emerging findings: IN insulin modulates neuroendocrine stress axes (reduced cortisol during psychosocial stress in healthy young men; decreased early-sleep cortisol in elderly but not young participants), sleep neurophysiology (enhanced EEG delta power in the second NREM cycle in young men), sensory perception (improved gustatory sensitivity; decreased olfactory sensitivity in some but not all studies), mood, and nicotine craving in smokers.
Methods
- Design: narrative review of the author's own and others' work, focused on human studies of IN insulin over roughly two decades; no systematic search or meta-analytic protocol is described.
- Data: proof-of-concept and (pilot) clinical investigations in healthy humans and patient cohorts (obesity, type 2 diabetes, MCI, Alzheimer's disease, smokers, major depressive disorder), plus supporting animal and post-mortem evidence.
- Analysis: qualitative synthesis organized by functional domain (CNS delivery route, metabolic effects, neuroendocrine/sleep effects, cognitive effects, sensory/mood/addictive behaviour), with a boxed summary of sex-difference findings.
Limitations
- Stated: some but not all studies point to sex differences in response to IN insulin that need further investigation, along with the impact of age; larger, systematic investigations are needed to identify relevant differences between men and women.
- Stated: further straightforward evidence for the central bioavailability of IN insulin (including in clinical cohorts such as type 2 diabetes or AD) would be welcome; some studies failed to detect CSF increases after IN insulin (lispro).
- Stated: the negative outcomes of longer-term IN insulin trials in obesity and Alzheimer's disease highlight the need for conceptual and methodological advances; the phase 2/3 trial suffered appliance-related hassles, and there is "lots of room for methodological improvements" in IN delivery.
- Stated: discrete functional, neurophysiological or neuroimaging-derived criteria for "brain insulin resistance" have not yet been established; many studies failed to establish a relationship between systemic insulin resistance/type 2 diabetes and molecular symptoms of neurodegenerative disease.
- Stated: the m-cresol excipient in most insulin formulations has a noticeable "coal tar" smell, requiring placebo carrier solution/diluent rather than odourless liquid to prevent unblinding and expectancy effects.
- Stated: there are currently no studies on IN insulin effects in transgender persons.
- Evident from the text: the review is non-systematic and author-selected, and many of the cited sex-difference findings come from small samples (as the paper itself notes).
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Claims the paper makes
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- Premisenone given§ Abstract
Longer-term IN insulin trials in individuals with obesity or Alzheimer's disease have negative outcomes.
“Still, the negative outcomes of longer-term IN insulin trials in individuals with obesity or Alzheimer's disease highlight the need for conceptual as well as methodological advances”
Quote in the paperSubstantial claim - Premisereasoning§ Abstract
IN insulin has a favourable safety profile for acute and repeated use.
“these studies moreover indicate a favourable safety profile of the acute and repeated use of IN insulin.”
Quote in the paperSubstantial claim - Premisecitation§ 1 | INTRODUC TI ON
Insulin receptors are found in high densities in the olfactory bulb, hypothalamus, cerebellum, hippocampus and connected limbic brain structures.
“insulin receptors are found in high densities in brain regions such as the olfactory bulb, hypothalamus and cerebellum, as well as in regions that enable memory formation, such as the hippocampus and connected limbic brain structures”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] source
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- Premisereasoning§ Abstract
The intranasal route enables delivery of insulin to the central nervous system with relative absence of systemic uptake and related peripheral side effects.
“The intranasal (IN) route enables the delivery of insulin to the central nervous system in the relative absence of systemic uptake and related peripheral side effects.”
Quote in the paperSubstantial claim - Premisenone given§ 1 | INTRODUC TI ON
The intranasal approach to deliver insulin to the brain has been successfully used in a large number of proof-of-concept and pilot clinical investigations.
“The intranasal (IN) approach to deliver insulin to the brain has been successfully used in a large number of proof-of-concept as well as (pilot) clinical investigations.”
Quote in the paperNot a substantial claim
- Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Other studies have failed to detect increases in cerebrospinal fluid after intranasal insulin lispro delivery to healthy volunteers.
“Considering that other studies have failed to detect increases in CSF after IN insulin delivery (albeit of the insulin analogue lispro) to healthy volunteers”
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- Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
In Sprague-Dawley rats, intranasally administered insulin-like growth factor-1 rapidly acts on multiple sites within the brain and spinal cord.
“Experiments in Sprague-Dawley rats relying on gamma counting and high-resolution phosphor imaging of tissue sections show that IN administered insulin-like growth factor-1 rapidly acts on multiple sites within the brain and spinal cord.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
Central nervous insulin signalling plays a major role in the regulation of eating behaviour and energy homeostasis.
“Central nervous insulin signalling plays a major role in the intricate regulation of eating behaviour and energy homeostasis.”
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- Interpretationnone given§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
The intranasal route of insulin administration largely avoids the methodological obstacles of systemic administration.
“The IN route of insulin administration largely avoids these methodological obstacles.”
Quote in the paperNot a substantial claim - Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Simple nasal atomisers have been proven to reliably trigger functional effects in healthy humans.
“simple nasal atomisers, 37 which have been proven to reliably trigger functional effects in healthy humans”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
In rats, transport along trigeminal nerve branches to brainstem regions has been demonstrated.
“In rats, transport along trigeminal nerve branches to brainstem regions has also been demonstrated.”
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- Premisereasoning§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Most insulin formulations used in IN insulin experiments contain m-cresol, an excipient with a distinct coal tar smell that is highly noticeable and sometimes unpleasant during IN use.
“The overwhelming majority of experiments in healthy participants and clinical cohorts performed so far have used insulin formulations (eg, Novolin R, Humulin R, Levemir) that contain m-cresol (meta-cresol), an excipient with a distinct”
Quote in the paperSubstantial claim - Interpretationcitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Because intra-neuronal transport of neuropeptides from the nasal cavity to the olfactory bulb takes several hours, intranasally administered peptides are more likely primarily transported along extra-neuronal routes.
“The intra-neuronal transport of neuropeptides from the nasal cavity to the olfactory bulb takes several hours, 29 which makes it more likely that IN administered peptides are primarily transported along extra-neuronal routes (ie, through intercellular clefts of the olfactory epithelium).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Until 2 November 2017, 38 studies on acute IN insulin administration at doses between 10 and 160 IU and including 1092 participants did not yield adverse events or cases of hypoglycaemia.
“Until 2 November 2017, 38 studies on acute IN insulin administration at doses between 10 and 160 IU and including 1092 participants did not yield adverse events or cases of hypoglycaemia.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
The animal findings that insulin acts in the brain to reduce food intake were repeatedly, although not unanimously, corroborated.
“These findings were repeatedly, 59,60 although not unanimously, 61 corroborated in animals.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
Brain uptake of IN insulin does not rely on absorption into the bloodstream and conventional blood-brain barrier transport of the hormone.
“These observations suggest that brain uptake of IN insulin does not rely on absorption into the bloodstream and”
Quote in the paperSubstantial claim - Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN S
The only symptomatic case of hypoglycaemia in long-term IN insulin studies was reported after administration of placebo spray.
“The only symptomatic case of hypoglycaemia in the long-term studies was reported after the administration of placebo spray.”
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- Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolism
In pancreatic clamps with a primed, constant infusion of glucose tracers, IN administration of 40 IU insulin lispro compared with placebo suppressed endogenous glucose production only in normal-weight participants.
“In the latter set of experiments, 83,84 the IN administration of 40 IU of insulin lispro, another rapid-acting insulin analogue, in comparison with placebo, suppressed endogenous glucose production only in the normal-weight participants.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
IN insulin administered to healthy women in the postprandial but not preprandial state reduced consumption and rated palatability of chocolate cookies offered after lunch.
“IN insulin administered to healthy women in the postprandial (but not in the preprandial) state reduced the consumption and rated palatability of chocolate cookies offered some time after lunch.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
Once-daily pre-sleep or post-sleep administration of 160 IU IN insulin for 8 weeks did not reduce body weight in healthy men.
“However, the once-daily pre-sleep (or, for that matter, post-sleep) administration of 160 IU of IN insulin for 8 weeks did not reduce body weight in healthy men”
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- Interpretationreasoning§ 3.1 | Food intake, body weight and energy expenditure
Delivery schedules synced to food intake might be necessary for the catabolic impact of IN insulin to emerge.
“suggesting that delivery schedules synced to food intake 39,42,44,47 might be necessary for the catabolic impact of IN insulin to emerge.”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationreasoning§ 3.1 | Food intake, body weight and energy expenditure
The finding that both young and elderly participants ate less after pre-sleep IN insulin implies that an acute enhancement of the central nervous insulin signal in the evening exerts a durable attenuating effect on food intake across sleep.
“This effect, which was found in young and elderly participants alike, implies that an acute enhancement of the central nervous insulin signal in the evening exerts a surprisingly durable attenuating effect on food intake across sleep as a period of relative metabolic inactivity.”
Quote in the paperSubstantial claim - Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
Recent experiments combining acute 40 IU IN insulin with a virtual grocery shopping task failed to find a hypophagic insulin effect in healthy young men.
“However, recent experiments that combined the IN administration of an acute dose of 40 IU of insulin with a virtual grocery shopping task failed to find a hypophagic insulin effect in healthy young men.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
In experiments with 160 IU IN insulin before nocturnal sleep, both men and women ate less from a standardised breakfast buffet when they had received IN insulin compared to placebo.
“In experiments investigating the impact of 160 IU of IN insulin administered before nocturnal sleep, both men and women ate less from a standardised breakfast buffet when they had received IN insulin compared to placebo.”
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- Interpretationcitation§ 3.2 | Glucose homeostasis and adipocyte metabolism
In individuals with obesity and/or type 2 diabetes, the brain is less sensitive to insulin.
“Thus, in individuals with obesity and/or type 2 diabetes, who suffer from variable degrees of peripheral insulin resistance, the brain is likewise less sensitive to insulin”
Quote in the paperSubstantial claim - Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
The loss of body fat in men after 8-week IN insulin was associated with a 27% reduction in circulating leptin concentrations.
“The loss of body fat in the men was associated with a 27% reduction in the circulating concentrations of leptin.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
In healthy normal-weight men, IN insulin 160 IU compared with placebo increases postprandial thermogenesis assessed via indirect calorimetry.
“In healthy normal-weight men, IN insulin (160 IU) vs. placebo increases postprandial thermogenesis assessed via indirect calorimetry”
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- Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolism
Overweight compared with normal-weight subjects display decreased MEG-assessed cortical activity during hyperinsulinaemic-euglycaemic clamps.
“overweight in comparison with normal-weight subjects display decreased MEG-assessed cortical activity during hyperinsulineamic-euglycaemic clamps”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
Pretreating healthy young men with transdermal oestrogen for three consecutive days, leading to a 3.5-fold increase in serum oestradiol, did not attenuate the suppression in calorie consumption triggered by IN insulin.
“pretreating healthy young men with transdermal oestrogen for three consecutive days, which led to a 3.5-fold increase in their serum oestradiol concentrations, did not attenuate the suppression in calorie consumption triggered by IN insulin.”
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- Interpretationcitation§ 3.1 | Food intake, body weight and energy expenditure
The timing of IN insulin delivery in relation to food intake may play an important role for its impact on energy intake.
“The timing of IN insulin delivery in relation to food intake may play an important role for its impact on energy intake”
Quote in the paperSubstantial claim - Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
Results and related fMRI experiments including men and women do not support the idea that sensitivity to the anorexigenic impact of insulin is reduced in females compared to males.
“These results and related experiments using functional magnetic resonance imaging (fMRI), 63 which included men and women, do not support the idea that the sensitivity to the anorexigenic impact of insulin is reduced in females compared to males.”
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- Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolism
Recent experiments suggest that IN insulin increases pancreatic insulin secretion, at least in participants with relatively high fMRI-assessed hypothalamic insulin sensitivity.
“Recent experiments moreover suggest that IN insulin increases pancreatic insulin secretion, at least in participants with a relatively high fMRIassessed hypothalamic insulin sensitivity.”
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- Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolism
Eight-week administration of IN insulin failed to affect body weight and fat mass in obese individuals.
“8-week administration of IN insulin failed to affect body weight and fat mass in obese individuals.”
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- Premisecitation§ 3.1 | Food intake, body weight and energy expenditure
In animals, intracerebroventricular insulin delivery increases locomotor activity.
“in animals, i.c.v.insulin delivery increases locomotor activity.”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Signs of reduced hypothalamic-pituitary-adrenal axis activity as a result of IN insulin were observed in human participants under resting conditions after 8 weeks of daily administration.
“Signs of reduced hypothalamic-pituitary-adrenal (HPA) axis activity as a result of IN insulin were, however, also observed in human participants under resting conditions after 8 weeks of daily administration.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
In acute paradigms, IN insulin (40 IU) vs placebo enhances odour-cued recall of spatial memory in male participants.
“enhancing effects of IN insulin (40 IU) vs. placebo on the odoor-cued recall of spatial memory were found in male participants 72”
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- Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
The same 40 IU IN insulin dose did not improve performance in 3D-simulated mazes and associated fMRI-assessed hippocampal activation.
“the same dose did not improve performance in 3D-simulated mazes and associated fMRI-assessed hippocampal activation, which was attributed to the potential influence of subtle differences in timing.108”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
IN insulin increased rather than decreased saliva cortisol concentrations during psychosocial stress in otherwise healthy smokers.
“By contrast, IN insulin increased rather than decreased saliva cortisol concentrations during psychosocial stress in experiments in otherwise healthy smokers.”
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- Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
Administering the rapid-acting insulin analogue insulin aspart intensifies the improvement in declarative memory.
“Administering the rapid-acting insulin analogue insulin aspart intensifies the improvement in declarative memory.40”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Post-hoc median-split analyses suggest that the declarative-memory effect of IN insulin is more pronounced in participants with relatively high compared to relatively low systemic insulin sensitivity.
“post-hoc median-split analyses of these results suggest that this effect is more pronounced in participants with relatively high compared to those with relatively low systemic insulin sensitivity.66”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
IN insulin administration before nocturnal sleep did not induce major changes in polysomnographically assessed sleep architecture in humans.
“Although IN insulin administration before nocturnal sleep did not induce major changes in polysomnographically assessed sleep architecture in humans, 45,46”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ BOX 1 (Continued)
IN delivery of 160 IU insulin reduces systemic lipolysis in healthy male individuals.
“Evidence for complementary functions of peripheral and CNS insulin in the regulation of whole-body energy homeostasis was also obtained in experiments showing that the IN delivery of 160 IU of insulin reduces systemic lipolysis in healthy male individuals.”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Acute IN insulin administration of 40 IU to healthy young men reduced the increase in saliva and plasma cortisol during a psychosocial stress test.
“Acute IN insulin administration (40 IU) to healthy young men reduced the increase in saliva, as well as plasma cortisol, during a psychosocial stress test.”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
In the same study, growth hormone concentrations showed a pronounced treatment-induced surge that was independent of the subject's sex.
“growth hormone concentrations showed a pronounced treatment-induced surge that was independent of the subject's sex.”
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- Interpretationreasoning§ BOX 1 (Continued)
The results may underpin the notion of a functional brain insulin-adipocyte axis.
“they may underpin the notion of a functional brain insulin-adipocyte axis.”
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IN insulin compared with placebo decreased cortisol concentrations in elderly but not young participants during the first half of the night in a sex-independent manner.
“IN insulin vs. placebo administration decreased the concentrations of cortisol in the elderly but not the young participants during the first half of the night in a sexindependent manner.”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
During early sleep, cortisol concentrations were generally higher in elderly compared to young participants.
“During early sleep, which is associated with the circadian nadir of HPA axis activity, cortisol concentrations were generally higher in the elderly compared to the young participants.”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
IN insulin compared to placebo enhances EEG delta power during the second 90 minutes of NREM sleep in young, healthy men.
“EEG delta power during the second 90 minutes of NREM sleep was found to be enhanced by IN insulin compared to placebo in young, healthy men.45”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Insulin secretion during the night is entrained to NREM sleep.
“The secretion of insulin during the night is entrained to NREM sleep 100 ;”
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- Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
The finding that IN insulin improves delayed declarative memory was replicated in obese men.
“This finding was later replicated in obese men.87”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Women displayed a trend to improved learning of new word-pairs in the insulin vs placebo condition.
“although women displayed a trend to improved learning of new word-pairs in the insulin vs. placebo condition; see below).45”
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- Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E S
Daily IN administration of 160 IU insulin vs placebo before nocturnal sleep triggers modest improvements in declarative memory after 5 weeks of treatment in healthy male individuals.
“the daily IN administration of 160 IU of insulin vs. placebo before nocturnal sleep triggers modest improvements in declarative memory after 5 weeks of treatment.66”
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
IN insulin in patients with type 2 diabetes enhances functional connectivity between prefrontal regions and the hippocampal formation.
“IN insulin was also found in patients with type 2 diabetes to enhance functional connectivity between prefrontal regions and the hippocampal formation.131”
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
Insulin is involved in activity-dependent processes of synaptic plasticity, namely long-term potentiation and long-term depression.
“It is also involved in activity-dependent processes of synaptic plasticity (ie, long-term potentiation [LTP] and long-term depression [LTD]).118”
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
Down-regulation of hippocampal insulin receptor function impairs LTP and spatial memory.
“Down-regulation of hippocampal insulin receptor function impairs LTP and spatial memory.120”
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- Interpretationreasoning§ 5.2 | Mediators of memory improvements upon IN insulin
IN insulin delivery may help overcome impairments in brain insulin signalling that are associated with systemic insulin resistance.
“IN insulin delivery may also help overcome impairments in brain insulin signalling that are associated with systemic insulin resistance.”
Quote in the paperSubstantial claim - Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
Studies in larger samples of male and female participants with cognitive impairments only yielded sporadic indicators of a sex difference in response to IN insulin.
“studies in larger samples of male and female participants with cognitive impairments only yielded sporadic indicators of a sex difference in the response to IN insulin, 74”
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
Insulin may boost brain energy supply via effects on astrocytes and other glia cells, including oligodendrocytes.
“Insulin may moreover boost brain energy supply via effects on astrocytes 129 and other glia cells, including oligodentrocytes.90”
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Insulin in the brain contributes to diverse neuronal signalling mechanisms, including catecholamine release and uptake, ion channel trafficking and regulation of receptors for neurotransmitters (γ-GABA, NMDA and AMPA).
“Insulin in the brain contributes to diverse neuronal signalling mechanisms, including catecholamine release and uptake, ion channel trafficking and the regulation of receptors for neurotransmitters (ie, γ-GABA, NMDA and AMPA).117”
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- Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
The recent multisite phase 2/3 clinical trial of IN insulin for MCI and AD faced unexpected methodological obstacles.
“the recent multisite phase 2/3 clinical trial of IN insulin for MCI and AD, which was conducted at 27 sites and included 289 participants (155 men) between 55 and 85 years of age with a diagnosis of amnestic MCI or AD, faced unexpected methodological obstacles.49”
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- Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disorders
A device for IN delivery that had been successfully used in previous studies proved unreliable in the first 49 participants because of malfunctions of a newly added electronic timer.
“A device for IN delivery that had been successfully used in previous studies 75,76,107 proved unreliable in the first 49 participants because of malfunctions of a newly added electronic timer.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation§ 5.2 | Mediators of memory improvements upon IN insulin
IN insulin may support impaired brain glucose turnover in patients with AD and at-risk individuals.
“In addition to improvements in insulin signalling, IN insulin may support impaired brain glucose turnover in patients with AD and at-risk individuals.143,144”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 7 | CON CLUDING REMARK S
A study in normal-or slightly overweight men yielded a dose-dependent enhancement of olfactory discrimination performance by IN insulin at doses of 40, 100 and 160 IU compared to saline.
“a study in normal-or slightly overweight men yielded a dose-dependent enhancement of olfactory discrimination performance by IN insulin (at doses of 40, 100 and 160 IU compared to saline).149”
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- Interpretationcitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOUR
IN insulin modulates reward-processing pathways that regulate motivated behaviour, including the hedonic drive to eat.
“The conclusion that IN insulin modulates reward-processing pathways that regulate motivated behaviour including the 'hedonic' drive to eat is in line with experiments in humans showing that IN insulin decreases the intake of palatable snacks.44”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] source
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- Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOUR
The dose-dependent effect of IN insulin on functional connectivity of the midbrain to the ventromedial prefrontal cortex in humans depends on systemic insulin sensitivity rather than BMI.
“the dose-dependent effect of IN insulin on functional connectivity of the midbrain to the ventromedial prefrontal cortex in humans depends on systemic insulin sensitivity (rather than BMI).161”
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
Chronic hyperinsulinaemia as in obesity and diabetes was observed in animal experiments to reduce the number of insulin receptors at the blood-brain barrier, thereby attenuating brain insulin uptake.
“Chronic hyperinsulinaemia as in obesity and diabetes was observed in animal experiments to reduce the number of insulin receptors at the BBB, 19 thereby attenuating brain insulin uptake.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19]
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- Premisecitation§ 7 | CON CLUDING REMARK S
The 8-week paradigm of IN insulin administration improved rated mood in normal-weight and obese participants.
“The 8-week paradigm of IN insulin administration described above improved rated mood in normal-weight,38 as well as obese participants.87”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ 7 | CON CLUDING REMARK S
There is enhanced sensitivity to cognitive effects of IN insulin in women.
“These intriguing findings corroborate the assumption of enhanced sensitivity to cognitive effects of IN in women and indicate a potential new role of IN insulin as a pharmacological adjuvant in cognitive-behavioural therapy of anxiety disorders, which, notably, have a higher prevalence in women.155”
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- Premisecitation§ 7 | CON CLUDING REMARK S
IN insulin administration (160 IU day−1 vs diluent for 4 weeks) to patients with major depressive disorder failed to improve measures of emotional wellbeing.
“IN insulin administration (160 IU day -1 vs. diluent for 4 weeks) to patients with major depressive disorder failed to improve measures of emotional wellbeing,156”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [156] source
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- Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulin
Many studies have failed to establish a relationship between systemic insulin resistance or type 2 diabetes and molecular symptoms of neurodegenerative diseases.
“many studies have failed to establish a relationship between systemic insulin resistance or type 2 diabetes and molecular symptoms of neurodegenerative diseases 142”
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- Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOUR
Connectivity analyses of neuroimaging results obtained in men and women have corroborated that IN insulin inhibits VTA-NAc projections.
“connectivity analyses of neuroimaging results obtained in men and women have corroborated that IN insulin inhibits VTA-NAc projections.63”
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- Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOUR
In healthy male participants, gustatory sensitivity to the tastes sweet, salty, bitter and sour was acutely improved by 40 IU IN insulin compared to placebo.
“In healthy male participants, gustatory sensitivity to the tastes sweet, salty, bitter and sour was acutely improved by 40 IU of IN insulin compared to placebo (diluent).146”
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- Interpretationcitation§ 7 | CON CLUDING REMARK S
Impaired CNS insulin signalling might contribute to the association between metabolic disorders such as obesity and diabetes and cognitive impairments, as well as dysthymia.
“Considering that impaired glucose tolerance as a result of diet-induced obesity abrogates the memory-improving and anxiolytic impact of insulin in mice, 152 impaired CNS insulin signalling might contribute to the association between metabolic disorders such as obesity and diabetes and cognitive impairments, as well dysthymia.156”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOUR
In otherwise healthy smokers, IN insulin (60 IU) compared with placebo reduced nicotine craving, even under conditions of psychosocial stress.
“In otherwise healthy smokers (with approximately 70%-80% of them being male), IN insulin (60 IU) in comparison with placebo reduced nicotine craving, even under conditions of psychosocial stress.96”
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- Interpretationcitation§ 7 | CON CLUDING REMARK S
IN insulin-induced improvements in odour-cued memory recall are not mediated via enhanced olfaction.
“These findings suggest the contribution of local effects on the olfactory epithelium and indicate that IN insulin-induced improvements (rather than impairments) in odour-cued memory recall72 are not mediated via enhanced olfaction.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [72] source
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- May combine two claims. 61
- Classified as probably not a substantial claim. 7
- The quote only partly states this claim. 1
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Premisenone given§ AbstractIN insulin modulates neuroendocrine activity, sleep-related mechanisms, sensory perception and mood.
“Emerging findings suggest that IN insulin also modulates neuroendocrine activity, sleep-related mechanisms, sensory perception and mood.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SThe blood-brain barrier is passively permeable to molecules smaller than 400 Da with fewer than eight to 10 hydrogen bonds and enables active, often saturable transport of bigger molecules.
“The BBB is passively permeable to molecules < 400 Da in size and with fewer than eight to 10 hydrogen bonds and enables the active, often saturable transport of bigger molecules.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] source
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Premisereasoning§ AbstractIN insulin exerts functional effects on cognition, including enhancements of memory performance in healthy individuals and patients with mild cognitive impairment or Alzheimer's disease.
“as well as cognition, ie, enhancements of memory performance both in healthy individuals and patients with mild cognitive impairment or Alzheimer's disease”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone given§ AbstractSome but not all studies point to sex differences in the response to IN insulin.
“Some, but not all studies point to sex differences in the response to IN insulin that need to be further investigated along with the impact of age.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone given§ AbstractIN insulin exerts functional effects on metabolism, including reductions in food intake and body weight and improvements of glucose homeostasis.
“Two decades of studies in healthy humans and patients have demonstrated that IN insulin exerts functional effects on metabolism, such as reductions in food intake and body weight and improvements of glucose homeostasis”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ 1 | INTRODUC TI ONCentral nervous insulin signalling contributes to peripheral energy and glucose homeostasis, growth and neuronal plasticity.
“central nervous insulin signalling contributes to functions as diverse as peripheral energy and glucose homeostasis, 6,7 growth 8 and neuronal plasticity.9”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
Premisecitation§ AbstractIntranasally administered insulin rapidly accumulates in cerebrospinal fluid, indicating efficient transport to the brain.
“Intranasally administered insulin is assumed to travel along olfactory and adjacent pathways and has been shown to rapidly accumulate in cerebrospinal fluid, indicating efficient transport to the brain.”
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Premisecitation§ 1 | INTRODUC TI ONInsulin concentrations in cerebrospinal fluid and plasma are correlated but much lower in cerebrospinal fluid.
“insulin concentrations in cerebrospinal fluid (CSF) and plasma are correlated but that insulin concentrations are much lower in CSF”
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SInsulin concentrations in cerebrospinal fluid increase during systemic infusion in men, indicating blood-to-brain transport.
“Its concentrations in the CSF increase during systemic infusion in men, 10 indicating blood-tobrain transport”
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SEighteen studies used chronic IN insulin administration with daily doses between 20 and 160 IU, or 0.5 and 1.5 U kg-1 body weight, for 21 days to 9.7 years, with 832 participants.
“Eighteen studies used chronic administration with daily doses of between 20 and 160 IU, or 0.5 and 1.5 U kg -1 body weight, for time periods between 21 days and 9.7 years with a combined number of 832 participants.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] source
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SWhen acutely administered to humans at cumulative doses up to 200 IU, IN insulin does not lead to large increases in systemic concentrations and appears to trigger side effects such as increases in cortisol and growth hormone only above this threshold.
“When acutely administered to humans at cumulative doses of up to 200 IU, IN insulin does not lead to large increases in systemic concentrations of the hormone 35 and appears to trigger side effects such as increases in cortisol and growth hormone only above this threshold.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [35] source
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- cites [50]
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Premisecitation§ 3.1 | Food intake, body weight and energy expenditureInsulin secretion peaks after food intake, and insulin is readily transported to the CNS where it rapidly elicits functional effects as indicated by EEG recordings in healthy men.
“Because insulin secretion peaks after food intake and the hormone is readily transported to the CNS 11 where it rapidly elicits functional effects as indicated by electroencephalogram (EEG) recordings in healthy men”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11]
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Interpretationreasoning§ 2 | THE INTR ANA SAL ROUTE TO THE CN SThe IN route is a non-invasive, easy-to-use and safe method for central nervous insulin delivery that has been regularly employed in preclinical and clinical experiments.
“In sum, the IN route is a non-invasive, easy-to-use and safe method for central nervous insulin delivery that has now been regularly employed in both preclinical and clinical experiments.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SIncreased body weight and possibly Alzheimer's disease appear to decrease the efficiency of blood-to-brain insulin transport.
“conditions such as increased body weight 20 and maybe also Alzheimer's disease (AD) 21,22 appear to decrease its efficiency.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [20]
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SThe safety findings were corroborated in related meta-analyses, and the most recent trial revealed no indicators of clinically relevant adverse events during daily administration of 40 IU insulin with two different administration devices.
“These findings were corroborated in related meta-analyses 54 and the most recent trial on IN insulin, 49 which revealed no indicators of clinically relevant adverse events during the daily administration of 40 IU of insulin with two different administration devices.”
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Interpretationcitation§ 3.1 | Food intake, body weight and energy expenditureInsulin might act as a satiety signal to inform the brain about acute energy intake and contribute to the postprandial decrease in appetite.
“insulin might act as a satiety signal to inform the brain about acute energy intake and contribute to the postprandial decrease in appetite.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58]
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Interpretationcitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SThe lack of changes in primary outcome measures of the most recent multisite phase 2/3 trial on IN insulin in individuals with mild cognitive impairment and Alzheimer's disease, which suffered appliance-related hassles, demonstrates room for methodological improvements in IN delivery.
“The lack of changes in primary outcome measures of the most recent multisite phase 2/3 trial on IN insulin in individuals with mild cognitive impairment (MCI) and AD that suffered from appliance-related hassles 49 (see below)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49]
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SIrritation of the nasal mucosa is the most commonly reported side effect of IN insulin, and the IN route for insulin delivery is safe and well-tolerated during acute and chronic use.
“It was concluded that irritation of the nasal mucosa is the most commonly reported side effect of IN insulin and that the IN route for insulin delivery is safe and well-tolerated both during acute and chronic use.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] source
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Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SIn healthy humans, intranasally administered insulin bypasses the blood-brain barrier and is detectable in cerebrospinal fluid within 1 hour after administration.
“Experiments in healthy humans have shown that IN administered insulin bypasses the BBB and is detectable in CSF within 1 hour after administration.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ 2 | THE INTR ANA SAL ROUTE TO THE CN SExposure to the smell of m-cresol might elicit expectancy effects with potential implications for behavioural outcomes.
“Moreover, also in parallel studies, exposure to the smell might elicit expectancy effects with potential implications for behavioural outcomes.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ 3.1 | Food intake, body weight and energy expenditureWoods et al. demonstrated in animals that insulin acts in the brain to reduce food intake, establishing insulin as an important adiposity signal.
“Woods et al. 23 demonstrated in animals, some 40 years ago, that insulin acts in the brain to reduce food intake, establishing insulin as an important adiposity signal that provides feedback from the body periphery to central nervous circuitries that control energy intake.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ 2 | THE INTR ANA SAL ROUTE TO THE CN SInsulin has a molecular weight of 5808 Da and depends on active transport mechanisms to enter the brain.
“Insulin has a molecular weight of 5808 Da and depends on active transport mechanisms to enter the brain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 18,,19
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Interpretationcitation§ 3.2 | Glucose homeostasis and adipocyte metabolismMimicking spillover by intravenous insulin aspart infusion yielded essentially identical changes in glucose homeostasis, raising the question of the relevance of CNS insulin for peripheral glucose homeostasis in humans.
“Mimicking this spillover by i.v.insulin aspart infusion yielded essentially identical changes in glucose homeostasis, raising the question of the relevance of CNS insulin for peripheral glucose homeostasis in humans.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50]
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Premisecitation§ 3.1 | Food intake, body weight and energy expenditureIn healthy, normal-weight humans, IN insulin administration for 8 weeks at 4 × 40 IU per day reduced body weight and body fat content in men, but not women.
“In healthy, normal-weight humans, IN insulin administration for 8 weeks (4 × 40 IU day -1 ) reduced body weight and body fat content in men, but not women.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] source
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Interpretationcitation§ BOX 1 (Continued)Brain insulin resistance might involve down-regulation or failure of insulin receptors and impairments of downstream signalling, and contribute to the emergence and/or persistence of metabolic dysregulation.
“it might involve the down-regulation or failure of insulin receptors, as well as impairments of downstream signalling, and contribute to the emergence and/or persistence of metabolic dysregulation”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [88]
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Interpretationreasoning§ 3.2 | Glucose homeostasis and adipocyte metabolismThe results support the assumption that CNS insulin signalling contributes to the regulation of systemic glucose and energy homeostasis in humans and that impaired peripheral insulin sensitivity impairs this effect.
“In sum, these results support the assumption that CNS insulin signalling contributes to the regulation of systemic glucose and energy homeostasis in humans and that impaired peripheral insulin sensitivity impairs this effect.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolismRepetitive IN insulin aspart delivery reduced plasma glucose concentrations, but at the same time small amounts of the insulin analogue entered the circulation.
“Repetitive IN insulin aspart delivery reduced plasma glucose concentrations, but at the same time small amounts of the insulin analogue entered the circulation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50]
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Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolismfMRI measurements indicated involvement of the hypothalamus and striatum in the glucoregulatory effects of IN insulin, which were not found in obese individuals.
“the fMRI measurements indicated an involvement of the hypothalamus and striatum in these glucoregulatory effects of IN insulin, which, notably, were not found in obese individuals”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [80] source
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Premisecitation§ 3.1 | Food intake, body weight and energy expenditureStudies in rodents suggest that systemic oestrogen may decrease the hypophagic effect of central insulin.
“although studies in rodents suggest that systemic oestrogen may decrease the hypophagic effect of central insulin”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] source
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Premisecitation§ 3.1 | Food intake, body weight and energy expenditureFasted men ate less after IN insulin 160 IU compared to placebo, whereas women consumed similar amounts of food in both conditions.
“fasted men ate less after IN insulin (160 IU) compared to placebo administration, whereas women consumed similar amounts of food from the breakfast buffet on offer in both conditions.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] source
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Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolismFindings in animals have established a role for central nervous insulin signalling in peripheral glucose homeostasis, mediated to some extent by hypothalamic astrocytes.
“Findings in animals have established a role for central nervous insulin signalling in peripheral glucose homeostasis, 77 which is mediated to some extent by hypothalamic astrocytes.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [77] source
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Interpretationcitation§ 3.2 | Glucose homeostasis and adipocyte metabolismThe outcome supports the concept of relative brain insulin resistance, defined as failure of brain cells to respond to insulin and implying that the central nervous insulin signal does not effectively support metabolic or cognitive functions.
“This outcome supports the concept of (relative)”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ 3.2 | Glucose homeostasis and adipocyte metabolismIN insulin improves hepatic energy metabolism in healthy humans but not in patients with type 2 diabetes.
“These outcomes expand findings that IN insulin improves hepatic energy metabolism in healthy humans but not in patients with type 2 diabetes”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [82] source
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersWomen, but not men, improved performance on declarative and working memory tasks after receiving 160 IU insulin vs placebo.
“women, but not men, improved their performance on declarative and working memory tasks after receiving 160 IU of insulin vs. placebo.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] source
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Interpretationreasoning§ BOX 1 (Continued)Taken together, the metabolic profile of IN insulin in humans comprises hypophagic/catabolic and glucoregulatory effects, which appear to be hampered by an association of metabolic impairments with reductions in brain insulin sensitivity.
“Taken together, the metabolic profile of IN insulin as derived from studies in humans comprises hypophagic/catabolic, as well as glucoregulatory effects, which, notably, appear to be hampered by an association of metabolic impairments with reductions in brain insulin sensitivity.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E SIN insulin compared to placebo did not alter retrieval of memory traces encoded before sleep but impaired acquisition of interfering memory contents on the next day.
“Insulin compared to placebo did not alter the retrieval of memory traces encoded before sleep but impaired the acquisition of interfering memory contents on the next day”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45]
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Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E SSystemic and i.c.v. insulin delivery extends NREM sleep duration in rodents but has opposite effects on REM sleep.
“systemic and i.c.v.insulin delivery extends NREM sleep duration in rodents but has opposite effects on REM sleep.101”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [101]
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Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E SThere is some experimental evidence that IN insulin modulates the activity of neuroendocrine stress axes and sleep neurophysiology.
“There is some experimental evidence for the assumption that IN insulin modulates the activity of neuroendocrine stress axes, as well as sleep neurophysiology.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ BOX 1 (Continued)Insulin administration decreased free fatty acid concentrations and lipolysis measured via appearance of deuterated glycerol, although it did not change lipolytic protein expression in biopsied subcutaneous adipose tissue.
“Insulin administration decreased free fatty acid concentrations and lipolysis measured via the appearance of deuterated glycerol, although it did not change lipolytic protein expression in biopsied subcutaneous adipose tissue.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [93]
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersEight weeks of IN insulin administration (4 × 40 IU day−1) to young men and women improved delayed recall of a list of 30 words encoded 1 week earlier, a measure of hippocampus-dependent declarative memory, whereas immediate word recall and non-declarative memory function remained unaffected.
“Eight weeks of IN insulin administration (4 × 40 IU day -1 ) to young men and women improved the delayed recall of a list of 30 words encoded 1 week earlier, a measure of hippocampus-dependent declarative memory, whereas immediate word recall and non-declarative memory function remained unaffected.38”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38]
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersIN insulin improves memory function in healthy humans and in individuals with memory impairments.
“The improving effect of IN insulin on memory function has been demonstrated in studies in healthy humans, [38][39][40]45,72 as well as individuals with memory impairments.[74][75][76][104][105][106][107]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [38]
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersIN insulin vs placebo before nocturnal sleep tended to improve acquisition of word-pairs on the subsequent evening in women, with opposite effects in men.
“IN insulin in comparison with placebo administration before nocturnal sleep tended to improve the acquisition of word-pairs on the subsequent evening in women, with opposite effects in men.45”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45]
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Premisecitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E SIncreases in HPA axis activity are associated with an increased risk for metabolic and cognitive impairments including Alzheimer's disease.
“Because increases in HPA axis activity are associated with an increased risk for metabolic and cognitive impairments including AD”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [99]
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Interpretationcitation§ 4 | EFFEC TS OF INTR ANA SAL IN SULIN ON NEUROENDO CRINE AND S LEEP-REL ATED PRO CE SS E SIN insulin impacts both nocturnal HPA axis activity and sleep-related neurophysiological mechanisms, effects that may contribute to the beneficial effect of IN insulin on memory function.
“Overall, these findings imply that IN insulin impacts both nocturnal HPA axis activity and sleep-related neurophysiological mechanisms, comprising effects that may contribute to the beneficial effect of IN inulin on memory function inasmuch as the consolidation of memory contents is known to benefit from sleep.103”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] source
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Premisecitation§ 7 | CON CLUDING REMARK SNo differences between insulin and placebo were observed in the primary measure (ADAS-cog-12) or in other clinical or CSF parameters in the phase 2/3 trial.
“No differences between insulin and placebo were observed in the primary measure (mean score changes on the Alzheimer Disease Assessment Scale-cognitive subscale 12, ADAS-cog-12 116 ) or in other clinical or CSF parameters”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [116]
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinThe establishment of hippocampal memory traces depends both on LTD and LTP.
“The establishment of hippocampal memory traces depends both on LTD and LTP, 119”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [119]
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinDeteriorations in the clearance and degradation of Aβ as a result of impaired insulin signalling are discussed as a mechanism that increases the risk of AD and may be improved by insulin administration.
“deteriorations in the clearance and degradation of Aβ as a result of impaired insulin signalling are discussed as a mechanism that increases the risk of AD 135 and may be improved by insulin administration.136,137”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ 7 | CON CLUDING REMARK SIn secondary analyses of participants who used the first nasal device, signs of improved ADAS-cog-12 scores were observed in the insulin group compared to placebo during both the blinded and open-label extension phase, along with increased Aβ42 to Aβ40 and Aβ42 to total tau ratios.
“in secondary analyses of the participants who used the first nasal device, signs of improved ADAS-cog-12 scores were observed in the insulin (n = 23) compared to the placebo group (n = 22) during both the blinded and open-label extension phase along with increased Aβ42 to Aβ40, as well as Aβ42 to total tau ratios.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49]
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinIn an ex vivo stimulation study, insulin signalling cascades in post-mortem hippocampal tissue from elderly individuals with or without AD (all without a history of diabetes) were strongly impaired in AD patients compared to controls matched for age and sex, and these impairments were negatively related to scores of cognition and memory.
“insulin signalling cascades in post-mortem hippocampal tissue from elderly individuals with or without AD 132 (all of them without a history of diabetes ) were strongly impaired in AD patients compared to controls matched for age and sex, and these impairments were negatively related to scores of cognition and memory.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [132] source
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersThe memory-improving impact of IN insulin does not essentially differ between postmenopausal women with reduced circulating oestrogen and young women on ethinyl oestradiol-dominant contraceptives, ruling out an influence of oestrogen signalling on sensitivity to insulin's memory effect.
“further experiments in healthy women showed that the memory-improving impact of IN insulin does not essentially differ between postmenopausal women with comparatively reduced circulating oestrogen and young women (on ethinyl oestradiol-dominant contraceptives), 43 ruling out an influence of oestrogen signalling on the sensitivity to insulin's memory effect”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43]
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Interpretationcitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersBrain insulin signalling is impaired, and may be effectively targeted by insulin administration, only in patients who do not carry the apoE ε4 allele.
“These observations suggest that brain insulin signalling is impaired (and may be effectively targeted by insulin administration) only in patients who do not carry the apoE ε4 allele, 113 a notion that has received support in subsequent trials.74,114”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [113]
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersSubsequent longer-term experiments confirmed the beneficial effect of IN insulin in memory-impaired individuals, both after 3 weeks and after 4 months.
“Subsequent longer-term experiments confirmed the beneficial effect of IN insulin in memory-impaired individuals, both after 3 weeks 106 and 4 months.75”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [106]
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersIn a 4-month trial in adults with amnestic MCI or mild to moderate AD, compared to placebo, story recall after 20 minutes was enhanced in the 20-IU but not the 40-IU insulin group, caregiver-rated functional ability was preserved in both insulin groups, and progression of hypometabolism was attenuated in both insulin groups.
“Compared to the placebo group, story recall after a delay of 20 minutes was enhanced in the 20-IU but not the 40-IU group, whereas caregiver-rated functional ability was preserved in both insulin-treated groups; moreover, the progression of hypometabolism assessed via 18 F fluorodeoxyglucose positron emission tomography was attenuated in both insulin groups.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [76]
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinInsulin potentiates NMDA receptor activity via delivery of NMDA receptors to the cell surface and NMDA receptor phosphorylation, processes that may trigger long-lasting meta-plastic changes.
“Insulin moreover potentiates NMDA receptor activity via delivery of NMDA receptors to the cell surface 121 and NMDA receptor phosphorylation, 122 processes that may trigger long-lasting meta-plastic changes.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [121]
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinEvidence for impairments in peripheral insulin signalling in patients with AD was presented more than 25 years ago, and the incidence of AD is increased in patients with metabolic impairments such as diabetes; some cognitive domains have been consistently found to be affected in type 2 diabetes.
“Evidence for impairments in peripheral insulin signalling in patients with AD was presented more than 25 years ago, 138 and the incidence of AD is known to be increased in patients with metabolic impairments such as diabetes 139,140 ; fittingly, some cognitive domains have been consistently found to be affected in type 2 diabetes (eg, memory, psychomotor speed, executive function).113”
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Premisecitation§ 5.1 | Memory function in healthy individuals and patients with memory disordersIn men and women with early AD or MCI, IN insulin vs placebo acutely improved declarative memory recall only in memory-impaired individuals without the apoE ε4 variant, whereas healthy controls did not benefit and memory-impaired apoE ε4 carriers showed signs of insulin-induced deteriorations.
“IN insulin compared with placebo acutely improved declarative memory recall only in memory-impaired individuals without the ɛ4 variant of the apolipoprotein E gene (ie, apoE ε4), a risk factor for sporadic AD, 112 whereas healthy controls did not benefit and memory-impaired apoE ε4 carriers even showed signs of insulin-induced deteriorations; follow-up studies yielded a comparable pattern.105”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [112] source
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinIN insulin delivery in healthy male individuals increases concentrations of high-energy phosphate compounds (ATP and phosphocreatine) in the motor cortex as assessed by 31P-magnetic resonance spectroscopy, an effect positively related to the subsequent insulin-induced decrease in food intake.
“IN insulin delivery has been shown in healthy male individuals to increase the concentrations of high-energy phosphate compounds (ie, ATP and phosphocreatine) in the motor cortex as assessed by 31 P-magnetic resonance spectroscopy, an effect that was positively related to the subsequent insulin-induced decrease in food intake.130”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [130]
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Interpretationreasoning§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOURThe characterisation of the complete action profile of IN insulin is an ongoing endeavour.
“the emerging literature on the impact of IN insulin on sensory processing, mood and addictive behavior illustrates that the characterisation of the complete action profile of IN insulin is an ongoing endeavour.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ 7 | CON CLUDING REMARK SThe lack of effects of long-term IN insulin delivery on metabolic control in obese individuals and on memory performance in patients with AD in larger trials highlights the need to determine whether the beneficial effects of IN insulin can be corroborated and eventually put to use in clinical settings.
“The lack of effects of long-term IN insulin delivery on metabolic control in obese individuals 87 and on memory performance in patients with AD in larger trials 49 highlights the need to determine whether the beneficial effects of IN insulin summarised here can be corroborated and eventually put to use in clinical settings.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [87]
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Premisecitation§ 7 | CON CLUDING REMARK SIN insulin (40 IU vs saline) acutely improved olfactory sensitivity in patients with post-infectious loss of smell, and twice-weekly IN insulin vs saline administration via gel foam placed in the olfactory cleft alleviated chronic hyposmia.
“IN insulin (40 IU vs. saline) acutely improved olfactory sensitivity in patients with post-infectious loss of smell,150 and twice-weekly IN insulin vs. saline administration via gel foam placed in the olfactory cleft alleviated chronic hyposmia.151”
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Premisecitation§ 7 | CON CLUDING REMARK SAcute induction of moderate euglycaemic hyperinsulinaemia in healthy individuals has been found to induce CNS inflammation and Aβ formation, both of which increase the risk of developing cognitive impairments.
“acute induction of moderate euglycaemic hyperinsulinaemia in healthy individuals has been found to induce CNS inflammation and Aβ formation, 115 both of which increase the risk of developing cognitive impairments.164”
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Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOURInsulin and nicotine exert synergistic effects on the hypothalamic melanocortin system and modulate dopaminergic pathways of the reward circuitry.
“Insulin and nicotine exert synergistic effects on the hypothalamic melanocortin system, 158 a major regulator of food intake, and modulate dopaminergic pathways of the reward circuitry.159,160”
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Premisecitation§ 7 | CON CLUDING REMARK SAcute IN administration of 160 IU insulin vs placebo enhanced fear extinction in healthy participants exposed to a differential fear-conditioning paradigm; in female but not male participants, IN insulin intensified the extinction-associated decrease in skin conductance responses.
“the acute IN administration of 160 IU of insulin vs. placebo enhanced fear extinction (ie, decreased fear-potentiated startle responses) in healthy participants exposed to a differential fear-conditioning paradigm; in the female but not the male participants, IN insulin moreover intensified the extinction-associated decrease in skin conductance responses.73”
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Premisecitation§ 5.2 | Mediators of memory improvements upon IN insulinRespective organ deficits in type 2 diabetes include reductions in hippocampal volume, ischaemic impairments and cortical hypometabolism.
“Respective organ deficits include reductions in hippocampal volume, 141 as well as ischaemic impairments and cortical hypometabolism.90”
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Premisecitation§ 7 | CON CLUDING REMARK SAnxiolytic behavioural effects of IN insulin have been demonstrated in mice and might be mediated by dopamine release triggered by insulin-induced changes in astrocyte gliotransmission in the nucleus accumbens.
“Anxiolytic behavioural effects of IN insulin have been demonstrated in mice 152 and might, for example, be mediated by dopamine release triggered by insulin-induced changes in astrocyte gliotransmission in the nucleus accumbens (NAc).153”
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Premisecitation§ 7 | CON CLUDING REMARK SSeven days of IN insulin administration attenuated anxiety-like behaviour in an elevated plus maze task in mice pre-treated with methamphetamine and decreased hippocampal markers of neuroinflammation.
“7 days of IN insulin administration attenuated anxiety-like behaviour in an elevated plus maze task in mice pre-treated with methamphetamine and decreased hippocampal markers of neuroinflammation.154”
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Premisecitation§ 6 | EFFEC TS OF INTR ANA SAL IN SULIN ON S EN SORY PRO CE SS ING , MOOD AND ADDIC TIVE B EHAVIOURAn individual IN dose of 40 IU insulin vs placebo decreased olfactory sensitivity as assessed by an olfactory threshold test using n-butanol in normosmic men and women but did not affect discrimination ability; in follow-up experiments in a larger sample, this effect was restricted to women.
“an individual IN dose of 40 IU of insulin vs. placebo (diluent) decreased olfactory sensitivity as assessed by an olfactory threshold test using n-butanol in normosmic men and women but did not affect discrimination ability 71 ; in follow-up experiments in a larger sample of normosmic participants, this effect was restricted to women.70”
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Interpretationreasoning§ 7 | CON CLUDING REMARK SIN insulin is a powerful experimental tool for investigating the role of brain insulin signalling in a plethora of functions and holds some promise for improving disorders of metabolism, cognition, and possibly also motivation and sensory processing.
“IN insulin is a powerful experimental tool for investigating the role of brain insulin signalling in a plethora of functions and holds some promise for improving disorders of metabolism, cognition, and possibly also motivation and sensory processing.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
Intranasally administered insulin travels along olfactory and adjacent pathways.
“Intranasally administered insulin is assumed to travel along olfactory and adjacent pathways”
The authors state this as an assumption.
Brain insulin for the most part derives from peripheral insulin crossing the blood-brain barrier by a saturable, receptor-mediated transport mechanism.
“it is assumed that brain insulin for the most part derives from peripheral insulin crossing the blood-brain barrier (BBB) by a saturable, receptor-mediated transport mechanism.”
The authors state this as an assumption.
The attenuating impact of brain insulin on HPA axis activity is mediated by enhanced corticosteroid feedback processing in the hippocampus.
“The attenuating impact of brain insulin on HPA axis activity, which diverges from the well-known stimulating impact of peripherally administered insulin, 97 has been assumed to be mediated by enhanced corticosteroid feedback processing in the hippocampus.”
The authors state this as an assumption.
Insulin benefits regional brain glucose uptake by activating the neuronal glucose transporter type 4 (GLUT4).
“insulin has been assumed to benefit regional brain glucose uptake by activating the neuronal glucose transporter (GLUT) type 4 (GLUT4), 124,125”
The authors state this as an assumption.
Dysfunctional brain insulin signalling may contribute to the development of AD independent of systemic failures in insulin signalling.
“There is some experimental support for the assumption that dysfunctional brain insulin signalling may contribute to the development of AD independent of systemic failures in insulin signalling”
The authors state this as an assumption.
IN insulin exerts some of its hypophagic effects by modulating the processing of the sensory qualities of food.
“which may also test the assumption that IN insulin exerts some of its hypophagic effects by modulating the processing of the sensory qualities of food.”
The authors state this as an assumption.
There may be a ∩-shaped function of IN insulin-induced memory improvements, such that above a certain threshold insulin may impair cognitive function, possibly by inducing inflammatory effects.
“These findings suggest that there may be a ∩-shaped function of IN insulin-induced memory improvements, an assumption that has received support in acute experiments 105 and might imply that above a certain threshold (that is yet to be identified) insulin may impair cognitive function, possibly by inducing inflammatory effects.115”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nasal insulin administration has been repeatedly used to study insulin action in the human brain.
“Nasal insulin administration has been repeatedly used to study insulin action in the human brain15.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [15]
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Xiao, C., Dash, S., Stahel, P., & Lewis, G. F. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13289 · Cited by 19 · see citing works
Santiago, J. C. P., & Hallschmid, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00054 · Cited by 18 · see citing works
Self-citationDifferential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans
Kern, W., Lieb, K., Kerner, W., et al. (1990) · Diabetes · doi:10.2337/diabetes.39.9.1091 · Cited by 18 · see citing works
Brünner, Y. F., Rodriguez-Raecke, R., Mutic, S., Benedict, C., & Freiherr, J. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.07.027 · Cited by 17 · see citing works
Insulin and Estrogen Independently and Differentially Reduce Macronutrient Intake in Healthy Men
Krug, R., Mohwinkel, L., Drotleff, B., Born, J., & Hallschmid, M. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01835 · Cited by 16 · see citing works
Self-citationOdor Sensitivity After Intranasal Insulin Application Is Modulated by Gender
Rodriguez‐Raecke, R., Brünner, Y. F., Kofoet, A., Mutic, S., Benedict, C., & Freiherr, J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00580 · Cited by 16 · see citing works
O-GlcNAcylation of Amyloid-β Protein Precursor by Insulin Signaling Reduces Amyloid-β Production
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Intranasal Insulin Boosts Gustatory Sensitivity
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State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease
Rhea, E. M., Leclerc, M., Yassine, H. N., Capuano, A. W., Tong, H., Petyuk, V. A., Macauley, S. L., Fioramonti, X., Carmichael, O., Calon, F., et al. (2023) · Aging and disease · doi:10.14336/ad.2023.0814 · Cited by 70 · see citing works
Intranasal Drug Administration in Alzheimer-Type Dementia: Towards Clinical Applications
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Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase
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Brain insulin responsiveness is linked to age and peripheral insulin sensitivity
Wagner, L., Veit, R., Kübler, C., Fritsche, A., Häring, H., Birkenfeld, A. L., Heni, M., Preissl, H., & Kullmann, S. (2023) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.15094 · Cited by 22 · see citing works
- Authors
- Hallschmid, M.
- Affiliations
- German Center for Diabetes Research (DE)
- Corresponding author
- Hallschmid, Manfred
- ORCID
- Hallschmid, Manfred
- Venue
- Journal of Neuroendocrinology
- Publisher
- Wiley
- Published
- 2021-01-28
- Volume
- 33
- Issue
- 4
- Pages
- e12934-e12934
- ISSN
- 0953-8194 (ISSN-L)
- 1365-2826
- OpenAlex
- W4206172179
- Semantic Scholar
- c7aeeab8341b2490a8fde40ed52e18328c323b94
- Cited by
- 113
- References
- 165
- Citations by year
- 2026: 26 · 2025: 22 · 2024: 23 · 2023: 19 · 2022: 17 · 2021: 6
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroendocrinology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
- Funders
- Bundesministerium für Bildung und Forschung (01GI0925)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Keywords
- intranasal insulin, brain insulin resistance, olfactory pathway, cerebrospinal fluid insulin, glucose homeostasis, dietary intake, body weight, memory, mild cognitive impairment, Alzheimer's disease, neuroendocrine activity, sleep, sex differences, obesity, type 2 diabetes, insulin signaling
- MeSH terms
- Administration, Intranasal, Body Weight, Brain, Cognition, Eating, Energy Metabolism, Humans, Insulin, Memory, Adipocytes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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