Intranasal Insulin For Alzheimer’s Disease Part 3

There is some experimental support for the assumption that brain insulin resistance may contribute to the development of AD independent of systemic failures in insulin signaling (as in type 2 diabetes) [e.g., 92, 167–169]. 

Diabetes is a serious metabolic disease that causes various adverse effects on organs throughout the body. One of these is the impact on brain function, including memory.

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Postmortem analyses of the brains of patients with AD have indicated decreases in messenger RNA and protein expression of insulin and insulin receptors as well as insulin-like growth factor-1 and insulin-like growth factor-2 along with signs of reduced downstream insulin signaling mechanisms that were related to disease markers of AD [167]. Such changes may trigger negative consequences for neuronal repair, dendritic sprouting, and differentiation [170] and impair neuronal plasticity via detrimental effects on glutamatergic and cholinergic pathways [137, 171]. 

In subsequent and very sophisticated analyses of post-mortem hippocampal tissues from elderly individuals with or without AD, without a history of diabetes, indicators of dysregulation of insulin signaling pathways were detected [168]: in a novel ex vivo stimulation paradigm, insulin signaling cascades were strongly impaired in the hippocampal tissue of patients compared with controls matched for age and sex, and these impairments were negatively related to scores of cognition and memory. 

In further post-mortem analyses of insulin signaling in the middle frontal gyrus cortex in 150 individuals (mean age at death, 87 years, 48% women), there were no differences between individuals with or without diabetes in IRS1 phosphorylation (pS307IRS1/total IRS1) and Akt phosphorylation (pT308Akt1/total Akt1); the latter was highly significantly associated with composite scores of AD pathology [172]. 

(In contrast to the previous findings from the same group [168], IRS1 serine phosphorylation was not found to be associated with cognitive AD pathology in this sample.) The concentration of insulin in the CSF of patients with AD appears to be an unresolved issue as some reports have indicated increased [173] or, on the contrary, reduced levels [174, 175], whereas other findings point to normal concentrations [176, 177]; the respective contribution of potential impairments in insulin production within the CNS is an intriguing, albeit debated issue [9, 11, 86, 103]. 

Deteriorations in the clearance and degradation of Aβ due to insulin resistance are discussed as a mechanism that increases the risk of AD [178] and may be improved by insulin administration [179–181]. In 3×TgAD mice, a rodent model of AD, IN insulin compared with placebo administration for 2 months improved measures of short-term memory (spatial learning in the Morris water maze test and novel object recognition), ameliorated depressive-like behavior (assessed by the tail suspension and the forced swim test), and decreased markers of disease pathology, i.e., tau phosphorylation in the hippocampus and frontal cortex as well as hippocampal concentrations of Aβ oligomers and 3-nitrotyrosine [182]. 

These findings extend previous observations in animal experiments (e.g., [83, 183]). Brain insulin resistance has also been assumed to be influenced by genetic factors in addition to and beyond apoE ɛ4. For example, subjects with the FTO gene polymorphism rs8050136 as well as carriers of the Gly972Arg polymorphism of IRS1 exhibit a decreased cerebrocortical response to intravenous insulin [184, 185].

4.3 Effectiveness and Safety of Intranasal Insulin for AD

Only one study so far has presented straightforward evidence for CSF uptake of insulin after IN delivery in humans [54]. 

Although studies in animals conclusively support the assumption that IN-administered substances (including insulin) are readily transported to the brain compartment [59], further experimental corroboration of the bioavailability of IN insulin, not least in patients with AD and related disorders as well as elderly individuals, would be welcome evidence for the effectiveness of IN insulin delivery. 

Nevertheless, respective experiments on other peptides such as oxytocin [186] corroborate the feasibility of IN peptide administration. Considering the lack of effects on primary outcome measures in the recent multi-site phase II/III clinical trial of IN insulin for MCI and AD [145], the currently available devices for IN drug delivery may benefit from further optimization [187]. 

The device used in that trial, which relies on a liquid hydrofuoroalkane propellant to eject a metered dose of insulin through a nose tip and achieved very high adherence rates, had not been previously tested in patients with AD but proved effective in animal experiments [59]. In this context, it should be noted that CSF increases after IN delivery of insulin [54] and a plethora of functional effects [62–65, 69, 72, 81, 114, 128, 188] in humans were observed in experiments that used a simple spray atomizer to initiate nose-to-brain transport of insulin. (Pharmacokinetic considerations notwithstanding, the same can be said of IN oxytocin [189]). 

Thus, it seems worthwhile to ponder if delivery devices that include more advanced, but maybe less robust or reliable, hardware or electronic components are essential to achieve successful brain uptake of IN-administered hormones. While specifically targeting the upper third of the nasal cavity to optimally reach the olfactory epithelium is certainly a worthwhile idea [59], functional MRI assessments of regional cerebral blood flow corroborate the effectiveness of basic nasal spray devices [190]. 

However, considering that advanced age [191] and cognitive impairments including AD [192] are associated with olfactory impairments that may be exacerbated by nasal membrane atrophy and nasal obstructions, efforts to improve the bioavailability of intranasally administered drugs are warranted. 

Relying on, for example, the use of nanoparticle carriers [193], cell-penetrating peptides [194], focused ultrasound [195], and other absorption enhancers [196], they have yielded promising results and might be expected to enhance the nasal uptake of insulin while maintaining the safety profile and low systemic exposure associated with IN administration.

Insulin treatment did not increase CSF insulin concentrations regardless of the administration device in the phase II/ III trial, but the measurements were made at single time points during baseline and after 12 months of administration; the authors conclude that direct (CSF- or imaging derived) proof of the ability of an IN device to target the CNS should best be collected before its use in clinical trials [145]. 

As a side note, it is worth mentioning a peculiar feature of IN insulin. All experiments in healthy participants and clinical cohorts described herein used insulin formulations (e.g., Novolin R, Humulin R, Levemir) that contain m-cresol (meta-cresol), an excipient with a distinct "coal tar" smell that is highly noticeable (and sometimes reported to be unpleasant) during IN use. 

In experiments with a crossover design [e.g., 63–65, 114, 128], it seems therefore mandatory to administer a diluent/carrier solution in the placebo condition to prevent premature unblinding. Although this precaution might appear of lesser relevance for parallel studies that expose participants to only one treatment [e.g., 70, 136, 138, 139, 143], it is conceivable that the intense smell of insulin solutions elicits stronger expectancy effects than a non-odorous placebo, with potential implications for cognitive outcomes (perhaps even in respective animal studies). 

In the recent phase II/III trial, this potential confounder was excluded by using a diluent for the placebo [145]. The principal effectiveness of enhancing memory function by boosting brain insulin signaling by IN insulin delivery in healthy participants, but also individuals with MCI or AD has been demonstrated in the studies discussed above. While signs of a modulating effect of apoE-ε4 on the neurofunctional impact of IN insulin in patients with AD have been repeatedly found ([134, 135, 138, 139]; see above) and animal experiments hint at potentially underlying mechanisms [197], systematic investigations in humans are needed to clarify the relevance of apoE-ε4 in the response to IN insulin [198], also about the role of brain glucose metabolism. 

Experiments relying on FDG-PET in middle-aged adults at risk of developing AD revealed an association between systemic insulin resistance and lower glucose metabolism in the left temporal medial lobe that predicted impaired immediate and delayed memory performance but did not interact with apoE-ε4 status; however, carriers of one or two ε4 alleles displayed decreased global glucose metabolism [199]. 

Mice carrying the apoE ɛ4 variant in comparison with controls carrying the ɛ2 allele, which is assumed to be protective, show reduced BBB glucose transport [200], suggesting that the higher AD risk in carriers of apoE ɛ4 may in part derive from reduced glucose transport into the brain [201]. Against the background of these and related reports of impaired brain glucose metabolism in AD ([e.g. [202, 203]), it might be speculated that insulin-induced enhancements of cognitive function in memory-impaired patients that occur within minutes at least in part derive from increases in cerebral glucose metabolism. 

However, considering that the absence of apoE ɛ4 appears to be a prerequisite for the cognitive impact of IN insulin, additional glucose-independent mechanisms are likely; it has also been argued that enhanced glucose uptake may mediate the acute effects of IN insulin whereas prolonged treatment may be necessary to induce improvements in synaptic plasticity [204]. In recent analyses of plasma samples obtained before and after 4 months of IN insulin vs saline administration to participants with MCI [205], favorable cognitive outcomes (ADAS-Cog) in response to the 20-IU dose of IN insulin [143] were mirrored by changes in neuronal extracellular vesicle biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1), which are known to be increased in patients with type 2 diabetes or AD and discussed as an easily accessible marker of brain insulin resistance [25]. 

This outcome, which appeared to be restricted to apoE ε4 non-carriers, suggests the engagement of the neuronal insulin cascade. A meta-analysis of the efficacy and acceptability of antidiabetic agents (IN insulin, pioglitazone, rosiglitazone, metformin, and liraglutide) for MCI and AD that comprised 19 studies published until January 2018 found that antidiabetic treatments overall improved cognitive performance [206]. Thus, approaches to overcome CNS insulin resistance might for example make use of the insulin-sensitizing effects of glucagon-like peptide-1 [207] or of metformin that is routinely prescribed for type 2 diabetes [208]. 

Metformin enhanced memory and decreased the concentrations of Aβ, hyperphosphorylated tau, and activated microglia in AD mouse models along with signs of improved insulin signaling in the brain [209, 210]. On the background of promising metformin effects on memory performance in individuals with MCI but without diabetes [211], a phase II trial (NCT04098666) in patients with MCI or AD is ongoing. 

While initial studies also boded well for the use of the peroxisome proliferator-activated receptor-ƴ agonist rosiglitazone [212], subsequent clinical trials did not indicate primary endpoint improvements in AD [213]. Moreover, a recent multi-site trial of pioglitazone in healthy participants aged 65 years or older with a high genotype-determined risk of developing cognitive impairments due to AD was terminated early for a lack of efficacy (NCT01931566 [214]). It should also be noted that lifestyle interventions to improve dietary habits [215] and increase physical activity [216] hold some promise to ameliorate cognitive impairments and AD, possibly via enhancements in brain insulin signaling. 

The safety profile of IN insulin has been systematically reviewed [58] (see [132, 217] for further reports). In 38 studies on acute IN insulin administration that included 1092 participants, no adverse events or cases of hypoglycemia were reported. Eighteen studies used long-term administration, with durations between 21 days and 9.7 years, and a combined number of 832 participants. 

The only symptomatic case of hypoglycemia in these studies was reported after administration of a placebo spray [218]. It was concluded that irritation of the nasal mucosa is the most commonly reported side effect and that the IN route for insulin administration is safe and well tolerated both during acute and chronic use. These findings were corroborated in related meta-analyses [206] and the most recent trial on IN insulin [145] that found no indicators of clinically relevant adverse events as a result of the daily administration of 40 IU of insulin with two different administration devices.

5 Concluding Remarks

Some caveats should be mentioned. Considering the hyperinsulinemia that accompanies peripheral insulin resistance, it might be argued that the (relative) reduction of CSF insulin observed in obese individuals [36] and, in some experiments, in patients with AD [174, 175], represents a protective mechanism limiting CNS hyperinsulinemia and potentially detrimental sequelae of cellular insulin resistance in CNS pathways. 

This speculative assumption is in line with the observations of dose-dependent effects of IN insulin administration on memory function discussed above acute IN insulin administration to individuals with AD improved verbal memory recall at lower (20 IU) but not higher doses (up to 60 IU); in carriers of the apoE ε4 allele, higher doses were even found to compromise memory performance [135]. Acute moderate euglycemic hyperinsulinemia in healthy individuals has been found to increase markers of CNS inflammation and Aβ formation [144], both of which increase the risk of developing cognitive impairments. 

However, pro-inflammatory in vitro effects on glial cells were found to vanish at higher insulin concentrations [219] and IN insulin decreased neuroinflammation and hippocampal lesion volume in a rat model of traumatic brain injury [28] (see [220, 221] for a discussion of insulin signaling and inflammatory processes in neurodegenerative disorders). The assumption that CNS hyperinsulinemia might promote brain insulin resistance is supported by in vitro experiments indicating that prolonged (4–24 h) exposure of hypothalamic cells to high insulin concentrations inactivate and degrade insulin receptors and IRS-1 [222]. 

Therefore, and against the background of the outcomes of most recent larger trials [145], it will be critical to investigate if the beneficial effects of acute and prolonged IN insulin administration can be corroborated and eventually put to use in the clinical setting, or if exogenous insulin delivery implies the risk of "induced brain insulin resistance." Moreover, there are many open questions regarding the mechanisms underlying and the implications of impaired brain insulin signaling in cognitive and metabolic disorders. 

They concern the relationship between AD and diabetes and brain concentrations of insulin, the factors that mediate cognitive impairments in metabolic disorders, and, not least, the question of whether neurodegeneration in AD can negatively affect the CNS control of systemic energy metabolism and contribute to systemic insulin resistance [86]. Regarding the use of IN insulin to prevent or counteract neurodegenerative disorders, future research may focus on several unresolved major issues:

Considering that (long-term) IN insulin delivery alone might be associated with gradual downregulation of CNS insulin sensitivity, may its combination with insulin sensitizers such as metformin be superior in boosting cognitive function? Should IN insulin be administered after improvements in (CNS) insulin sensitivity have been achieved in patients with cognitive impairments and metabolic comorbidities via conventional means such as lifestyle intervention, so that resulting gains in brain functions can be preserved?

Which delivery approaches and devices are optimally suited to enable nose-to-brain transport of insulin and other drugs, particularly in the clinical setting? Which absorption enhancers are best equipped to maximize brain permeation of IN insulin, and which doses, dosing schedules, insulin formulations, or insulin analogs are needed for the optimization of the memory effect?

To what extent do mechanisms related to olfaction and sensory perception contribute to memory improvements after IN insulin delivery? Do sleep-related and circadian neurophysiological and neuroendocrine processes and stress-related psychoneuroendocrine factors modulate the impact of IN insulin in a (clinically) relevant manner?

Does the cognitive (as well as metabolic) response to IN insulin critically depend on age and sex, and if so, how can future treatment approaches relying on IN insulin be tailored to the individual needs of patients?
In sum, while the bulk of experimental work outlined in this review underlines the effectiveness of IN insulin in improving memory function, there is still some work to be done to avoid pitfalls and fulfill the potential of IN insulin for AD.

Declarations

Funding Open Access funding enabled and organized by Projekt DEAL. This work was supported by grants from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.; 01GI0925).

Conflicts of interest/Competing interests Manfred Hallschmid has received honoraria and/or travel reimbursements from Boehringer Ingelheim, Germany, Lilly UK, and Novo Nordisk, Denmark. These relationships did not affect the preparation of the article.

Ethics approval is Not applicable.

Consent to participate is Not applicable.

Consent for publication is Not applicable.

Availability of data and material Not applicable.

Code availability is Not applicable.

Authors' contributions MH performed the literature search and conceived, drafted, and revised the work.

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