Intranasal insulin effect on cognitive and/or memory impairment: a systematic review and meta-analysis

Abstract

Background: Cognitive impairment, characterized by deficits in cognitive functions and loss of delayed and immediate recall, disproportionately affects individuals aged 65 years and older, particularly those with comorbid cardiovascular conditions such as hypertension and diabetes mellitus. Objective: This study aimed to investigate the potential association between intranasal insulin and cognitive and/or memory impairment, with a specific focus on delayed and immediate recall, considering the rising prevalence of cognitive disorders in the aging population. Methodology: Employing a rigorous systematic approach, we conducted a thorough search of MEDLINE, Scopus, the Cochrane database, and Web of Science from inception to November 23, 2022, identifying relevant randomized clinical trials. Our analyses encompassed three key aspects: (i) assessing the impact of intranasal insulin on cognitive impairment, (ii) evaluating its effect on delayed recall, and (iii) examining its influence on immediate recall. Results: Five studies meeting the inclusion criteria were included. The results underscored a statistically significant effect of intranasal insulin on delayed memory (effect size: 1.37; 95% CI: 0.65 to 2.09) and overall cognition (effect size: 0.58; 95% CI: 0.08 to 1.08). However, no statistically significant effect was observed for immediate memory (effect size: 0.48; 95% CI: -0.00 to 0.96). Conclusions: This study provides compelling evidence supporting the significance and efficacy of intranasal insulin in enhancing delayed recall and overall cognition. The observed effects hold promise for potential therapeutic interventions in addressing cognitive deficits associated with aging and comorbid conditions. The findings emphasize the need for further research to elucidate the underlying mechanisms and optimize the application of intranasal insulin in cognitive enhancement strategies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11571-024-10138-5.

Introduction

Mild cognitive impairment (MCI) is a clinical syndrome that encompasses a heterogeneous group of cognitive impairments beyond what is expected for normal aging but does not reach the diagnostic criteria for dementia (Petersen et al. 2014). MCI can manifest in various cognitive domains, including memory, attention, language, and executive function, among others (Petersen et al. 2014; Albert et al. 2011). One specific subtype of MCI, known as amnestic MCI, is characterized by memory deficits, particularly in the domain of episodic memory, while other cognitive functions remain relatively intact (Petersen et al. 2014; Albert et al. 2011). MCI is recognized as an intermediate stage between normal cognitive functioning and the development of dementia, such as Alzheimer’s disease (AD) (Petersen et al. 2014).

The prevalence of MCI and AD has been steadily increasing in recent years due to advancements in healthcare and the aging of the population (Prince et al. 2013; Satizabal et al. 2016). With the aging demographic, there is a growing interest in understanding the risk factors associated with cognitive impairment and identifying potential interventions to delay or prevent progression to dementia (Prince et al. 2013; Satizabal et al. 2016). Numerous studies have investigated the risk factors for MCI and AD, including age, genetics, cardiovascular risk factors, lifestyle factors, and comorbidities such as diabetes and hypertension (Saczynski et al. 2008, Gottesman et al. 2014; Rizzi et al. 2014).

In recent years, there has been significant progress in identifying potential interventions for cognitive impairment and MCI. Research has focused on lifestyle modifications, cognitive training programs, pharmacological interventions, and combinations of these approaches (Ngandu et al. 2015, Kivipelto et al. 2020; Petersen et al. 2018). These interventions aim to improve cognitive function, delay cognitive decline, and reduce the risk of progression to dementia (Ngandu et al. 2015, Kivipelto et al. 2020; Petersen et al. 2018). The development of effective interventions for MCI is of great importance, as early detection and timely intervention may help optimize cognitive function and improve the quality of life for individuals at risk of developing dementia (Petersen et al. 2014).

In addition to age-related changes in cognition, older adults often experience multiple comorbidities that can impact cognitive function. Conditions such as hypertension, hypercholesterolemia, dyslipidemia, and diabetes mellitus (DM) are frequently observed among the elderly population. Among these comorbidities, diabetes mellitus has been of particular interest due to its association with an increased risk of developing dementia and cognitive dysfunction. Studies have shown that individuals with diabetes mellitus have a 1.5- to 2.5-fold higher risk of developing dementia than those without diabetes (Gomez-Gujarro et al. 2023). Specifically, type 2 diabetes mellitus (T2DM) has been implicated in cognitive changes that primarily affect learning and memory, mental flexibility, and processing speed (Janson et al. 2004). These cognitive impairments may arise due to the complex interplay of factors such as insulin resistance, chronic hyperglycemia, vascular damage, and the accumulation of amyloid-beta plaques in the brain. Understanding the cognitive impact of diabetes mellitus, particularly type 2 diabetes mellitus, is crucial for developing targeted interventions and preventive strategies to mitigate the risk of cognitive decline and dementia in older adults.

Growing evidence suggests that T2DM is closely linked to cognitive impairment, including MCI and the progression to dementia. The pathophysiological mechanisms underlying this association involve chronic hyperglycemia, insulin resistance, and dysregulation of glucose metabolism in the brain (Cheng et al. 2012, Morris et al. 2014). Furthermore, T2DM-related cerebrovascular changes, such as microvascular lesions and cerebral hypoperfusion, contribute to the cognitive decline observed in these individuals (Kester et al. 2014; Li et al. 2023). Given the rising prevalence of T2DM and its detrimental impact on cognitive function, it is crucial to explore potential interventions, such as intranasal insulin, to mitigate cognitive impairment in this population.

Beyond its role in glucose metabolism, insulin has emerged as a key player in various central functions. It is involved in the regulation of energy metabolism, neuroendocrine control, memory formation, and neural survival (Ezkurdia et al. 2023). Studies have shown that individuals with AD exhibit reduced insulin receptor levels in the brain (Ezkurdia et al. 2023). Advancements in diabetes management have led to the development of novel types of insulin and routes of administration. Intranasal insulin has gained attention as an alternative delivery method due to its ease of administration and potential cognitive benefits in individuals with DM (Zhang et al. 2015). Intranasal insulin delivery has shown promise as a potential therapeutic approach for improving cognitive function and memory impairment in individuals with DM and neurodegenerative disorders such as AD. Animal studies have demonstrated that intranasal insulin can enhance hippocampus-dependent memory and synaptic plasticity, leading to improved cognitive performance (Craft et al. 2012; Fihurka et al. 2023). Furthermore, clinical trials have reported beneficial effects of intranasal insulin on memory, attention, and executive functions in individuals with MCI and AD (Reger et al. 2008; Claxton et al. 2013). These findings suggest that intranasal insulin may exert its cognitive benefits by directly modulating insulin signaling pathways in the brain, thereby improving neural function and promoting neuroprotection.

Previous systematic reviews have explored the use of intranasal insulin in improving cognitive function (Shemesh et al. 2012). However, these reviews did not provide a quantitative analysis of the effect of intranasal insulin on cognitive outcomes. Hence, the objectives of this systematic review and meta-analysis are twofold: (i) to investigate the association between intranasal insulin and cognitive impairment, including delayed and immediate recall, and (ii) to explore potential moderating factors such as age, sex, type of insulin, and duration of follow-up. By conducting a comprehensive analysis, we aim to provide a clearer understanding of the effects of intranasal insulin on cognition in individuals with MCI or at risk of developing dementia.

To accomplish these objectives, we will systematically search and analyse relevant studies, including randomized controlled trials and observational studies, that have investigated the effects of intranasal insulin on cognitive outcomes (delayed and immedaite recall and cognition). The data obtained will be synthesized using appropriate statistical methods, such as meta-analysis and meta-regression, to determine the overall effect size and examine potential sources of heterogeneity. Additionally, we will assess the quality and risk of bias in the included studies to ensure the validity and reliability of our findings.

This systematic review and meta-analysis will contribute to the literature by providing a comprehensive analysis of the association between intranasal insulin and cognitive impairment. The results will help elucidate the potential benefits of intranasal insulin as a therapeutic intervention for cognitive deficits in individuals with MCI or at risk of developing dementia. Furthermore, the identification of moderating factors will aid in tailoring interventions to specific populations. Ultimately, the findings from this study may have important implications for clinical practice and the development of novel treatment strategies for cognitive impairment.

Materials and methods

This systematic review and meta-analysis followed rigorous methodological standards to ensure transparency, reproducibility, and accuracy in the synthesis of evidence. The study protocol was registered in the PROSPERO database under the registration number CRD42021252356, which helps to prevent duplication and increase transparency in the research process. The methods employed in this review adhered to the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al. 2011). This comprehensive resource provides a framework for conducting systematic reviews and meta-analyses, offering guidance on study selection, data extraction, risk of bias assessment, and statistical analysis. Furthermore, the reporting of this review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Me-ta-Analyses (PRISMA) statement (Moher et al. 2010). The PRISMA statement provides a standardized checklist for reporting systematic reviews and meta-analyses, ensuring the clear and comprehensive reporting of study methods, results, and conclusions (Table S1).

Search strategy

A systematic search of the Medline database (via PubMed), Scopus, Cochrane Library, and Web of Science was conducted from inception to November 23, 2022. The search strategy included the following relevant terms: (1) “intranasal administration”, “intranasal insulin”, “central insulin administration”, (2) “declarative memory”, “memory”, “cognition”, “memory impaired”, “memory improving” and “spatial memory”. The literature search was complemented by reviewing the references of the articles considered for inclusion in this systematic review and meta-analysis.

Study selection

The included studies in this analysis were selected based on specific inclusion and exclusion criteria. The inclusion criteria encompassed the following: (i) randomized clinical trials (RCTs), which are considered the gold standard for evaluating intervention effects; (ii) adult participants, indicating that the studies involved individuals who were 18 years of age or older; (iii) studies that utilized intranasal insulin as an intervention, focusing on the administration of insulin through the nasal route; (iv) studies that measured both delayed and immediate recall, allowing for the assessment of memory functions at different time points; and (v) studies that assessed cognitive functions before and after the treatment, enabling the evaluation of cognitive changes following intranasal insulin intervention.

On the other hand, certain exclusion criteria were applied to ensure the selection of high-quality and relevant studies. These criteria consisted of the following: (i) articles published in languages other than English or Spanish, limiting the analysis to studies available in these two languages; (ii) exclusion of nonrandomized clinical trial designs, as they are prone to various biases and may provide less reliable evidence; and (iii) exclusion of duplicate reports of the same study to avoid duplication of data.

In cases where multiple studies provided data on the same sample, priority was given to the study that presented the most detailed results or had the largest sample size. However, if different reports provided complementary information on the sample characteristics, data from multiple reports were extracted to obtain a comprehensive understanding of the study population. The literature search was conducted independently by two reviewers (MDGG and ICR), and inconsistencies were resolved by consensus and with the participation of a third researcher (ASL).

Data extraction and risk of bias assessment

The following data were extracted from the original reports: (1) reference (author and year of publication), (2) country, (3) study population characteristics (number of participants, age, diseases), (4) intervention characteristics (type of insulin, dose, duration), and (5) cognition and memory delayed and immediate recall outcomes (Cognition and memory test and measured construct [cognition, memory delayed or immediate recall]). Additionally, information was extracted from the articles regarding the duration of the intervention, the tests that were measured with their baseline and post-intervention values and which constructs they measure.

The Cochrane Risk of Bias 2 (RoB2) assessment tool was utilized to evaluate the risk of bias in the included randomized controlled trials (RCTs) [28]. This tool comprises five domains that assess different aspects of potential bias: (i) bias in the randomization process; (ii) bias due to deviations from intended interventions; (iii) bias due to missing outcome data; (iv) bias in the measurement of outcomes; and (v) bias in the selection of reported outcomes (Sterne et al. 2019). The overall risk of bias was determined based on the assessment of these domains. If all domains were categorized as “low risk,” the overall risk of bias was considered “low risk of bias.” If at least one domain was classified as “some concerns,” the overall risk was categorized as “some concerns.” On the other hand, if any domain was classified as “high risk” or several domains were assessed as “some concerns” that affected the validity of the results, the overall risk of bias was labelled “high risk of bias” (Sterne et al. 2019).

Data extraction and risk of bias assessment were conducted independently by two researchers (MDGG and ICR), and inconsistencies were resolved by consensus with the involvement of a third researcher (ASL).

Statistical analysis and data synthesis

A comprehensive meta-analysis was conducted to evaluate the impact of intranasal insulin on cognitive function and delayed and immediate recall. The DerSimonian and Lair and Hartung-Knapp-Sidik-Jonkman random-effects method was employed to calculate the pooled effect size (ES) along with its corresponding 95% confidence interval (95% CI) (DerSimonian et al. 2007, IntHout et al. 2014)]. The degree of heterogeneity among the included studies was assessed using the I2 test, where I2 values were interpreted as follows: negligible (0–30%); moderate (30–50%); substantial (50–75%); or considerable (75–100%) heterogeneity (Higgins et al. 2011). The associated p values were also taken into consideration.

To ensure the robustness of the findings and identify potential sources of heterogeneity, sensitivity analyses were performed. These analyses aimed to assess the stability of the summary estimates and identify any particular study that may have significantly influenced the observed heterogeneity. Additionally, subgroup analyses were conducted to examine the effects of intranasal insulin on delayed and immediate memory separately. Furthermore, random-effects meta-regressions were employed to investigate whether factors such as age, sex, type of insulin, and duration of follow-up had an impact on the results.

Publication bias, which refers to the potential selective publication of studies, was evaluated using Egger’s test (Sterne et al. 2001) and through visual inspection of funnel plots. These methods were employed to assess whether there was a possibility of bias in the included studies, as publication bias can affect the validity and generalizability of the meta-analysis results.

Results

Characteristics of the included studies

Five randomized clinical trials were included in this systematic review to investigate the impact of intranasal insulin on cognitive impairment, delayed and immediate recall (Fig. 1). These trials, conducted between 2008 and 2020, varied in duration from 8 weeks to 12 months and were carried out in Germany (Benedict et al. 2004; Hallschmid et al. 2008; Ritze et al. 2018) and the United States (Craft et al. 2012, 2020). The combined sample size comprised 448 participants (34.97% female) aged 18 to 85 years.

Fig. 1.

Flowchart of the identification, screening, eligibility, and inclusion of studies. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools

Intranasal insulin administration protocols differed across studies, involving distinct insulin types and intranasal devices. Insulins used included Actrapid1 HM (Benedict et al. 2004; Hallschmid et al. 2008), Novolin R, Novo Nordisk (Craft et al. 2012), Insulin, Humulin-RU-100, Lilly (Craft et al. 2020), and Insulin Actrapid; Novo Nordisk (Ritze et al. 2018). The study durations ranged from 8 weeks to 4 years. The timing of intranasal insulin administration also varied, with two studies administering it during breakfast and dinner (Craft et al. 2020; Ritze et al. 2018) and others at different times, including noon, afternoon (30 min before eating), and bedtime (Benedict et al. 2004; Hallschmid et al. 2008). Tests employed to assess cognitive impairment, delayed, and immediate recall included word list, word-stem priming, Stroop test, and mood assessment across studies (Table 1). Additionally, Table 2 showed the duration of the interventions, the baseline and follow up values of all tests included and which constructs they measured: cognition, memory delayed or immediate recall.

Table 1.

Characteristics of the Included Studies

Reference	Country	Design	Characteristics of the population			Characteristics Intervention				Outcomes
			n	Ages	Type disease	Type insulin	Dosage	Number of times	Duration	Cognition and memory tests	Measurred construct
Benedict et al. 2004	Germany	Randomized clinical trial	38 (24 males)	18–34	Healthy	Insulin Actrapid1 HM, Novo Nordisk, vehicle (HOE 31 dilution buffer for H-Insulin, Aventis Pharma, Bad Soden, Germany	160 UI (40 UI x4 times)	In the morning, around noon, in the evening and before going to bed	8 weeks	*Word list * Wordstem priming * Stroop test * Mood assessment	Immediate and delayed recall
Craft et al. 2012	United States	Randomized clinical trial	104	72.5	64: MCI 40: AD	Novolin R; Novo Nordisk. ViaNase nasal drug delivery device (Kurve Technology, Bothell, Washington	Placebo: 30 (17 male) 20 UI: 36 participant 40 UI: 38 participants	Breakfast and dinner	4 months	*Delayed story recall *DSRS * ADAS-cog * ADCS-ADL	Delayed recall and cognition
Craft et al. 2020	United States	Randomized clinical trial	240 (123 men)	55 to 85 70.9 [7.1]	Healthy	Insulin Humulin-RU-100; Lilly device 1 (ViaNase; Kurve Technology)	40 UI IG1(121): Insulin IG2(119): Placebo	NA	12 months	ADAS-cog-12 Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment (ADL- MCI)	Valuates memory, attention, reasoning, language, orientation, and praxis. Cognition and daily function)
Hallschmid et al. 2008	Germany	Randomized clinical trial	30	(insulin: 33.5 [1.3] years, placebo: 33.9 [2.2] years	Obesity	Insulin Actrapid HM, Novo Nordisk, Mainz, Germany) vehicle (HOE 31 dilution buffer for H-Insulin, Sanofi-Aventis, Frankfurt, Germany	160 UI IG1(15): Insulin IG2(15): Place	In the morning, around noon, in the evening and before going to bed	8 weeks	Word list Wordstem priming task	Memory declarative No memory declarative
Ritze et al. 2018	Germany	Randomized clinical trial	36 (male)	18–40	Healthy	Insulin Actrapid; Novo Nordisk, Mainz, Germany	160 UI IG1 (12): Placebo morning IG2(12): INS morning IG3(12): INS evening.	Morning and evening	8 weeks	Word list WordStem Priming	Declarative memory Nondeclarative memory

**Data are shown as the mean standard deviation (SD) or interquartile range (IR); NA: not available; ADAS-cog: Alzheimer Disease Assessment Scale–cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study– activities of daily living; DSRS: Dementia Severity Rating Scale; IG: intervention group

Table 2.

Baseline and follow up values of the cognirtion and memory test included in the studies

	Duration	Measure construct	Insulin	Placebo	Insulin	Placebo
			Baseline		Follow-up
Benedict et al. 2004	8 Weeks	Inmediate memory	Neutral: 4.14 ± 0.29 Emotion: 4.11 ± 0.30 Food: 3.25 ± 0.35 All words: 11.60 ± 0.65	Neutral: 4.34 ± 0.29 Emotion: 4.31 ± 0.30 Food: 3.17 ± 0.35 All words: 11.67 ± 0.65	Neutral: 4.50 ± 0.47 Emotion: 4.72 ± 0.39 Food: 4.45 ± 0.44 All words: 13.82 ± 0.85	Neutral: 4.14 ± 0.45 Emotion: 4.83 ± 0.42 Food: 4.65 ± 0.41 All words: 13.48 ± 0.81
		Delayed memory	Neutral: 2.87 ± 0.47 Emotion: 3.04 ± 0.45 Food: 1.78 ± 0.34 All words: 7.68 ± 1.06	Neutral: 2.66 ± 0.47 Emotion: 3.23 ± 0.45 Food: 2.01 ± 0.34 All words: 7.89 ± 1.06	Neutral: 2.20 ± 0.37 Emotion: 2.29 ± 0.45 Food: 1.75 ± 0.42 All words: 6.20 ± 1.03	Neutral: 0.86 ± 0.36 Emotion: 0.94 ± 0.44 Food: 1.08 ± 0.41 All words: 2.94 ± 1.00
Craft et al. 2012	4 months	Delayed memory	20UI 1.86 (0.17) 40UI 1.99(0.17)	20UI 2.25(0.19) 40UI 2.25(0.19)	20UI 2.11(0.18) 40UI 1.90(0.18)	20UI 2.14(0.20) 40UI 2.14(0.20)
		Cognition	DSRS score: 20UI 1.72 (0.16) 40UI 1.78 (0.17)	DSRS score: 20UI 1.64(0.19) 40UI 1.64(0.19)	DSRS score: 20UI 1.62(0.17) 40UI 1.72(0.18)	DSRS score: 20UI 1.89(0.20) 40UI 1.89(0.20)
			ADAS- cog score: 20UI 2.21 (0.12) 40 UI 2.26 (012)	ADAS- cog score: 20UI 1.93(0.13) 40 UI 1.93(0.13)	ADAS- cog score: 20UI 2.27(0.11) 40 UI 2.31(0.11)	ADAS- cog score: 20UI 2.11(0.13) 40 UI 2.11(0.13)
			ADCS- ADL scale score: 20UI 3.79 (0.03) 40UI 3.77 (0.03)	ADCS- ADL scale score: 20UI 3.75(0.03) 40UI 3.75(0.03)	ADCS- ADL scale score: 20UI 3.77(0.03) 40UI 3.76(0.03)	ADCS- ADL scale score: 20UI 3.68(0.04) 40UI 3.68(0.04)
Craft et al. 2020	12 months	Cognition	ADAS-cog-12-score: 25.91 (8.28)	ADAS-cog-12-score: 24.73 (7.56)	ADAS-cog-12-score: NA	ADAS-cog-12-score: NA
Hallschmid et al. 2008	8 weeks	Delayed memory	Sum 4.24 ± 0.64 Food: 1.69 ± 0.33 Emotional: 1.62 ± 0.25 Neutral: 0.93 ± 0.20	Sum: 3.88 ± 0.56 Food: 1.06 ± 0.23 Emotional: 1.38 ± 0.27 Neutral: 1.44 ± 0.30	Sum 2.87 ± 0.56 Food: 1.01 ± 0.36 Emotional: 1.50 ± 0.37 Neutral: 0.36 ± 0.20	Sum 1.13 ± 0.38 Food: 0.35 ± 0.15 Emotional: 0.57 ± 0.24 Neutral: 0.21 ± 0.12
		Inmediate memory	Sum: 8.44 ± 0.61 Food:3.25 ± 0.35 Emotional:3.25 ± 0.30 Neutral:1.94 ± 0.32	Sum: 7.69 ± 0.57 Food: 2.63 ± 0.22 Emotional: 2.75 ± 0.39 Neutral: 2.31 ± 0.37	Sum 8.13 ± 0.78 Food: 2.87 ± 0.38 Emotional: 3.40 ± 0.48 Neutral: 1.87 ± 0.27	Sum 7.73 ± 0.64 Food: 2.73 ± 0.27 Emotional: 2.87 ± 0.29 Neutral: 2.13 ± 0.38
Ritze et al. 2018	8 weeks	Delayed memory	Food-related: - Morning: 0.93 ± 0.41 - Evening: 1.06 ± 0.41 Emotional: - Morning: 1.39 ± 048 - Evening: 2.25 ± 0.46 Neutral: - Morning: 1.47 ± 0.30 - Evening: 1.15 ± 0.31 All words: - Morning: 3.84 ± 0.81 - Evening; 4.56 ± 0.82	Food-related: - Morning: 1.84 ± 0.41 - Evening: 1.846 ± 0.41 Emotional: - Morning: 1.44 ± 046 - Evening: 1.44 ± 0.46 Neutral: - Morning: 1.47 ± 0.30 - Evening: 1.47 ± 0.30 All words: - Morning: 4.60 ± 0.82 - Evening; 4.60 ± 0.82	Food-related: - Morning: 0.72 ± 0.36 - Evening: 1.08 ± 0.33 Emotional: - Morning: 1.31 ± 0.31 - Evening: 1.635 ± 0.32 Neutral: - Morning: 1.05 ± 0.41 - Evening: 1.02 ± 0.42 All words: - Morning: 3.13 ± 0.78 - Evening; 3.85 ± 0.80	Food-related: - Morning: 1.19 ± 0.33 - Evening: 1.19 ± 0.33 Emotional: - Morning: 0.98 ± 031 - Evening: 0.98 ± 0.31 Neutral: - Morning: 0.96 ± 0.41 - Evening: 0.96 ± 0.41 All words: - Morning: 3.03 ± 0.78 - Evening; 3.03 ± 0.78
		Inmediate	Food-related: - Morning: 3.25 ± 0.37 - Evening: 3.29 ± 0.32 Emotional: - Morning: 3.54 ± 0.26 - Evening: 4.17 ± 0.37 Neutral: - Morning: 3.08 ± 034 - Evening: 3.46 ± 0.4 All words: - Morning: 9.88 ± 0.83 - Evening; 10.92 ± 0.71	Food-related: - Morning: 3.79 ± 0.37 - Evening: 3.79 ± 0.37 Emotional: - Morning: 4.42 ± 0.34 - Evening: 4.42 ± 0.34 Neutral: - Morning: 3.50 ± 0.40 - Evening: 3.50 ± 0.40 All words: - Morning: 11.71 ± 0.89 - Evening; 11.71 ± 0.89	Food-related: - Morning: 3.76 ± 0.45 - Evening: 4.07 ± 0.44 Emotional: - Morning: 4.36 ± 0.47 - Evening: 3.93 ± 0.46 Neutral: - Morning: 3.50 ± 0.55 - Evening: 4.26 ± 0.55 All words: - Morning: 11.83 ± 1.11 - Evening; 12.27 ± 1.08	Food-related: - Morning: 3.83 ± 0.45 - Evening: 3.83 ± 0.45 Emotional: - Morning: 4.63 ± 0.47 - Evening: 4.63 ± 0.47 Neutral: - Morning: 4.15 ± 0.55 - Evening: 4.15 ± 0.55 All words: - Morning: 12.40 ± 0.81 - Evening; 12.40 ± 1.10

NA: not available

In Table 3, we present a comparative analysis of previous and current research, shedding light on critical aspects of intranasal insulin interventions across various populations. Benedict et al. (Benedict et al. 2004) observed a statistically significant improvement in both immediate and delayed recall in the general population, specifically highlighting the efficacy of intranasal insulin in enhancing memory functions. Craft et al. (Craft et al. 2012), focusing on patients with AD and MCI, demonstrated significant improvements in long-term memory and overall cognition, providing valuable insights into the potential benefits for this specific population. Additionally, the study by Hallschmid et al. (Hallschmid et al. 2008) among patients with obesity revealed enhanced declarative memory and improved mood, albeit without statistical significance in short-term or long-term memory. In our current research, encompassing diverse populations, we observed a very high effect of intranasal insulin on improving delayed recall and a high effect on enhancing overall cognition.

Table 3.

Comparative Analysis of Previous and Current Research in the Literature Review Section: Identifying Research Gaps

Study	Population		Intervention	Duration	Test Cognition	Test Memory	Measuring	Outcomes	Relevant Finding
Previous research
Benedict et al. 2004	N: 38 Age:18–34	General population	Insulin intranasal (Various Types)	8 weeks	NA	*Word list * Wordstem priming * Stroop test * Mood assessment	*Immediate and delayed recall	Improved immediate and delayed recall	Statistical significance in delayed recall, but not in immediate recall
Craft et al. 2012	N:104 Age media: 72.5	Patient with AD and MCI	Insulin intranasal (Various Types)	4 months	*DSRS * ADAS-cog * ADCS-ADL	*Delayed story recall	NA	Improved delayed recall and preserved general cognition	Statistical significance in long-term memory and improvement in cognition
Craft et al. 2020	N:240 Age: 55–85	General population	Insulin intranasal	12 months	*ADAS-cog-12 *ADL- MCI	NA	*Valuates memory, attention, reasoning, language, orientation, and praxis Cognition and daily function)	No statistically significant results were observed	No statistically significant in cognition
Hallschmid et al. 2008	N: 30	Patient with obesity	Insulin intranasal (Various Types)	8 weeks	NA	*Word list *Wordstem priming task	*Memory declarative *No memory declarative	Improved declarative memory and mood improved	Not statistically significant in short-term or long-term memory
Ritze et al. 2018	N:36 Age:18–40	General population	Insulin intranasal (Various Types)	8 weeks	NA	*Word list *WordStem Priming	*Declarative memory *Nondeclarative memory	Improved in delayed recall and cognition when intranasal insulin is administered at night	Statistical significance in delayed recall, but not in immediate recall
Current research
Gómez-Guijarro et al. 2023	N: 448 Age:18–85	Patient with AD, MCI, obesity, and general population	Insulin intranasal (Various Types)	8 weeks − 12 months	*DSRS * ADAS-cog * ADCS-ADL *ADAS-cog-12 *ADL- MCI	* Stroop test * Mood assessment *Delayed story recall *Wordstem priming task *Word list *WordStem Priming	Immediate and delayed recall *Valuates memory, attention, reasoning, language, orientation, and praxis. Cognition and daily function) *Memory declarative *No memory declarative	Improved delayed recall and cognition	Very high effect of intranasal insulin on improving delayed recall and high on improving cognition

NA: not available; MCI: mild cognitive impairment; AD: Alzheimer’s disease; AD: ADAS-cog: Alzheimer’s Disease Assessment Scale–cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study– activities of daily living; DSRS: Dementia Severity Rating Scale; IG: intervention group; ADL-MCI: Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment

Risk of bias

The risk of bias in the included studies, as assessed with RoB2, indicated some concerns, particularly in the randomization process and the selection of the reported outcome domain. However, all studies had a low risk of bias in the randomization process, except for one that showed some concerns of bias (Figure S1).

Effect of intranasal insulin on cognitive impairment and delayed and immediate recall

The meta-analysis revealed a pooled effect size (ES) of 0.39 (95% CI: -0.39 to 1.00) for the effect on cognitive and/or memory impairment, with substantial heterogeneity between studies (I-squared = 81.3%, p = 0.000) (Fig. 2).

Fig. 2.

Pooled for the effect on cognitive and/or memory impairment

Moreover, the pooled ES for the effect of intranasal insulin on cognitive impairment and delayed and immediate recall was as follows: (i) 1.37 (95% CI: 0.65 to 2.09) for delayed memory; (ii) 0.48 (95% CI: -0.00 to 0.96) for immediate memory, and (iii) 0.58 (95% CI: 0.08 to 1.08) for cognition. Considerable heterogeneity was observed for the intranasal insulin effect (I2 = 90.0%) (Fig. 3).

Fig. 3.

Meta-analysis for the effect of intranasal insulin on cognitive impairment and delayed and immediate recall

Sensitivity analysis and meta-regressions

Sensitivity analysis and meta-regressions demonstrated that the pooled ES estimates were not significantly modified when individual studies were removed from the analysis. Random-effects meta-regression models for the effect on delayed memory, immediate memory, and cognition indicated that percentage of women (p = 0.320), length of follow-up (p = 0.261 ) and age (p = 0.590) were not related to heterogeneity across studies. (Figure S2, Figure S3, Figure S4 and Figure S5)

Publication Bias

Publication bias, assessed by Egger’s test and funnel plot asymmetry, did not significantly impact delayed memory (p = 0.504), immediate memory (p = 0.792), or cognition (p = 0.226) (Figure S6, Figure S7, Figure S8).

Discussion

This systematic review and meta-analysis aims to provide comprehensive insights into the impact of intranasal insulin on cognition and delayed recall. Previous systematic reviews have explored the use of intranasal insulin to enhance cognitive function but failed to quantify its effects on cognitive outcomes (Zhang et al. 2015). In contrast, our study goes beyond assessing cognitive function improvement to specifically examine the influence of intranasal insulin on delayed recall. Our results showed a very high effect of intranasal insulin on improving delayed recall and a high effect on improving cognition. Moreover, factors such as age, dose, percentage of women, and duration of follow-up did not seem to influence the effects of insulin on cognition or both delayed and immediate recall.

Another systematic review and meta-analysis investigated the efficacy of intranasal insulin on cognition in individuals with mild cognitive impairment (MCI) or dementia, but no significant differences were found between the intranasal insulin and placebo groups (Long et al. 2022). However, in our systematic review and meta-analysis, we conducted a separate analysis of the amount of intranasal insulin administered. To the best of our knowledge, this study represents the first quantitative analysis examining the association between intranasal insulin, delayed and immediate recall, and cognition. Notably, our comprehensive meta-regressions considering age, dose, percentage of women, and duration of follow-up failed to identify any substantial impact of these factors on the effects of insulin on cognition and delayed and immediate recall.

Existing systematic reviews have highlighted the potential increased risk of cognitive impairment associated with type 2 diabetes (Mattishent and Loke 2016). Insulin resistance, a common factor shared by both type 2 diabetes and cognitive impairment, plays a crucial role in brain energy metabolism and cognitive function (Kellar and Craft 2020). Such resistance may be due to a negative regulation of insulin receptors, which are unevenly distributed throughout the brain and may differ between specific brain regions (Nijssen et al. 2023), which may differ between specific brain regions, such as the olfactory bulb, cerebral cortex, hypothalamus and hippocampus (AboEl-Azm et al. 2023). Intranasal insulin administration circumvents the blood‒brain barrier, a protective mechanism that shields the brain from harmful substances. By utilizing extracellular pathways, intranasal administration facilitates the rapid delivery of insulin to the central nervous system through olfactory neurons. Within a mere 30 min, insulin reaches the cerebrospinal fluid without being absorbed into the bloodstream (Andreasen et al. 2023). Insulin binds to receptors present in the previously mentioned regions, which are keys involved in declarative memory formation and the conscious recall of facts and events and are integral to the limbic system. Multiple studies have demonstrated the involvement of insulin signaling in memory regulation and cognition (Chen et al. 2014; Crowe et al. 2018).

The intricate interplay between cognition and memory disruption, particularly concerning the effects of intranasal insulin, involves a nuanced network of brain regions (Erichsen et al. 2020; Erichsen et al. 2021). Existing evidence underscores the crucial connection between disruptions in cognitive processes and memory functions, accentuating the multifaceted neural mechanisms at play (Hrybouski et al. 2023). The established association between cognitive impairment and memory disruption, as illuminated in the context of intranasal insulin interventions, manifests through intricate neural processes (Long et al. 2022). Cognitive functions, encompassing memory encoding, retrieval, and overall cognitive performance, are intricately linked (S. K et al. 2023). Disruptions in cognitive domains often parallel disturbances in memory processes, creating a symbiotic relationship that warrants detailed exploration (Bradley-Garcia et al. 2022). The neural substrate underlying the effect of intranasal insulin on cognition and memory prominently involves specific brain regions (Long et al. 2022; Benedict et al. 2007). The literature points to the centrality of regions such as the hippocampus, known for its pivotal role in memory consolidation and spatial learning (Shinohara et al. 2023). The hippocampus, susceptible to insulin modulation, has emerged as a key player in mediating the impact of intranasal insulin on memory-related processes (Erichsen et al. 2020). Additionally, the prefrontal cortex, a hub for executive functions and higher cognitive processes, stands implicated in the intricate balance between cognition and memory. Insulin sensitivity within the prefrontal cortex is suggested to influence cognitive performance, with potential implications for memory disruptions (Klune et al. 2021). The amygdala, recognized for its role in emotional memory processing, further contributes to the intricate relationship between cognition and memory (Zhang 2022). Insulin’s influence on the amygdala may underpin emotional aspects of memory, adding a layer of complexity to the observed cognitive and memory effects (Long et al. 2022). Furthermore, the default mode network (DMN), a network of interconnected brain regions engaged during rest and self-referential thinking, has emerged as a focal point in understanding cognitive and memory interactions (Mastrovito et al. 2023). Disruptions in the DMN, potentially modulated by intranasal insulin, could contribute to alterations in cognitive and memory-related processes (Long et al. 2022). Beyond regional considerations, the interplay between cognition and memory involves intricate neurotransmitter systems and synaptic plasticity (Yang et al. 2023). Insulin’s impact on neurotransmitter release, particularly involving acetylcholine and glutamate, may contribute to the observed cognitive and memory effects (Kellar et al. 2020). Synaptic plasticity mechanisms, including long-term potentiation (LTP) and long-term depression (LTD), further underscore the dynamic neural adaptations influencing cognitive and memory processes (Valdivia et al. 2023).

The underlying neural mechanism for the effect of intranasal insulin on cognitive and/or memory impairment involves intricate processes within the central nervous system (Gaddam et al. 2021). Insulin, traditionally recognized for its metabolic role, has emerged as a crucial player in neural function. Its impact is particularly notable in brain regions implicated in cognitive processes (Duarte 2023). The neural mechanism encompasses the interaction between insulin and its receptors, triggering cascades of intracellular events (Kumar et al. 2021). Activation of insulin receptors influences synaptic plasticity, neurotransmitter release, and neuronal survival. In the hippocampus, a region vital for memory formation, insulin modulates long-term potentiation (LTP) and synaptic transmission, fundamental processes underpinning learning and memory (Valdivia et al. 2023). Insulin resistance, observed in conditions such as type 2 diabetes, may disrupt these finely tuned processes (Yudhani et al. 2023). Negative regulation of insulin receptors could compromise neuronal responsiveness, potentially contributing to cognitive impairment. This dynamic interplay between insulin, its receptors, and neural pathways underscores the intricate nature of the neural mechanism governing the effects of intranasal insulin on cognitive and memory functions (Long et al. 2022).

Recent studies have suggested a potential link between intranasal insulin administration and the regulation of brain-derived neurotrophic factor (BDNF), a protein involved in neuronal growth and synaptic plasticity. BDNF is known to play a crucial role in memory consolidation and cognitive function (Marosi and Mattson et al. 2014, Lu et al. 2014). Intranasal insulin has been shown to increase BDNF levels in the hippocampus, a brain region closely associated with memory formation (Chapman et al. 2013). These findings suggest that the observed improvements in delayed recall following intranasal insulin administration may be mediated, at least in part, by the upregulation of BDNF. Moreover, emerging evidence supports the notion that intranasal insulin may have direct effects on neuronal activity and neurotransmitter systems involved in memory processing. Animal studies have shown that intrana-sal insulin administration can enhance the release of acetylcholine in the hippocampus, a neurotransmitter critical for learning and memory (McIntyre et al. 2012). In addition, insulin has been found to modulate the activity of gamma-aminobutyric acid (GABA), a neurotransmitter involved in the inhibition of neural excitability and synaptic plasticity (Kosukegawa et al. 2023). These neurochemical changes induced by intranasal insulin may contribute to the observed improvements in delayed recall.

While our systematic review and meta-analysis provide valuable insights into the effects of intranasal insulin on cognition and memory, it is important to acknowledge several limitations that may impact the generalizability and interpretation of our findings. First, the limited number of studies available for inclusion in our analysis restricts the robustness and generalizability of our conclusions. The scarcity of studies specifically comparing the effects of intranasal insulin on both delayed and immediate recall hinders our ability to draw definitive conclusions regarding its efficacy in different memory domains. Second, the variations in the methods of intranasal insulin administration across the included studies introduce potential sources of variability in the observed effects. Differences in dosage, timing, and duration of administration may influence the outcomes and limit the comparability of the studies. Third, the heterogeneity in the variables used for adjustment in each study, such as age, comorbidities, and baseline cognitive function, adds complexity to the interpretation of our results. These differences in principal characteristics and adjustment variables may contribute to the observed heterogeneity and influence the overall conclusions. Furthermore, the use of diverse cognitive assessment scales among the included studies introduces another source of heterogeneity. Variations in the sensitivity, specificity, and domains assessed by these different scales may affect the comparability and synthesis of the results. Last, the majority of the included studies exhibited a moderate risk of bias, suggesting the potential for systematic errors that may impact the validity of the reported findings. The presence of bias highlights the need for cautious interpretation and underscores the importance of further high-quality studies in this field.

This systematic review and meta-analysis shed light on the effects of intranasal insulin on cognition and delayed recall. The observed improvement in delayed recall provides promising evidence of the potential therapeutic benefits of intranasal insulin. Despite certain limitations, our findings contribute to the growing body of literature in this field. Further research is warranted to address the identified limitations and provide more definitive insights into the effects of intranasal insulin on cognition and memory. Such knowledge holds significant implications for the development of targeted interventions and treatment strategies for individuals experiencing cognitive deficits or at risk of developing dementia.

In this study we also wanted to analyze in parallel and at the same time jointly the effect of intranasal insulin on memory either short-term memory which is characterized by retaining a limited amount of information for a short period of time and long-term memory mechanism that allows encoding and retaining an unlimited amount of information over a long period of time (Cowan 2008). Declarative memory is a type of long-term memory, which is affected in the early stages of AD (Jahn, 2013). In addition, obese men are sensitive to the enhancing effects of intranasal insulin on neuropsychological functions, these in turn are directly related to suffering from type 2 diabetes mellitus. As we have discussed previously, T2DM is associated with the development of cognitive impairment, which is associated with memory loss and memory impairment.

Research gaps and highlights

Research into the effects of intranasal insulin on cognitive function and memory, particularly delayed recall, addresses a critical research gap in our understanding of potential interventions for cognitive impairment, especially in conditions such as MCI and AD. The rise in the prevalence of MCI and AD underscores the urgency to explore innovative approaches to delay cognitive decline and mitigate the risk of dementia. While previous studies have examined risk factors for cognitive impairment, including DM, the intricate connection between DM, specifically T2DM, and cognitive decline necessitates targeted investigations.

Based on the information provided in Table 2, we can emphasize the distinctiveness of our approach compared to previous studies by highlighting the following points: (1) Our study encompasses a significantly broader range of participants, including individuals with AD, MCI, obesity, and individuals from the general population. This contrasts with previous studies that typically focused on one specific population group, such as the general population or patients with AD and MCI; (2) We have employed a comprehensive assessment battery that evaluates various cognitive domains and daily functioning, including tests such as the DSRS, ADAS-cog, ADCS-ADL, ADAS-cog-12, and ADL-MCI. This comprehensive approach allows for a thorough evaluation of the effects of intranasal insulin across multiple cognitive and functional domains, which sets our study apart from previous research efforts; (3) Our study extends the duration of the intervention period, ranging from 8 weeks to 12 months. This longer duration allows for a more robust assessment of the sustained effects of intranasal insulin on cognitive function and daily living activities, providing valuable insights into the long-term efficacy of this intervention; (4) While previous studies have primarily focused on immediate and delayed recall as measures of memory function, our study expands upon this by including a broader range of memory assessments, such as the Stroop test, mood assessment, delayed story recall, wordstem priming task, and word list. This comprehensive approach enables us to thoroughly evaluate the impact of intranasal insulin on different aspects of memory function.

This systematic review and meta-analysis focuses on intranasal insulin as a potential intervention, considering its ease of administration and promising cognitive benefits observed in both animal studies and clinical trials. The study aims to bridge existing gaps by not only assessing cognitive outcomes but also conducting a quantitative analysis of the impact on delayed and immediate recall. The diverse methodologies and administration protocols across the included studies, such as variations in insulin types, dosage, and timing, underscore the complexity of this field and emphasize the need for a comprehensive analysis. In justifying the rationale behind combining data from Alzheimer’s disease (AD)/mild cognitive impairment (MCI), obesity, and healthy individuals for analysis, it’s essential to highlight the potential benefits of such an inclusive approach. Firstly, this comprehensive sampling strategy allows for a more holistic understanding of the effects of the intervention across diverse populations, thereby enhancing the generalizability of findings. By including individuals with varying cognitive statuses and metabolic profiles, we can better elucidate the potential differential responses to the intervention, providing valuable insights into its efficacy across different health conditions. Moreover, this approach facilitates the identification of potential interactions or synergistic effects between cognitive impairment, metabolic dysfunction, and overall health status, which may not be apparent in studies focusing solely on one population group. Ultimately, by integrating data from diverse populations, we can uncover nuanced patterns and refine our understanding of the intervention’s mechanisms of action, paving the way for more tailored and effective therapeutic strategies in clinical practice.

The intricate relationship between cognition and memory disruption, particularly regarding the effects of intranasal insulin, is explored through a nuanced examination of neural mechanisms. The involvement of brain regions such as the hippocampus, prefrontal cortex, amygdala, and the DMN is highlighted. Moreover, the impact of insulin on neurotransmitter systems, synaptic plasticity, and the regulation of BDNF adds layers to our understanding of how intranasal insulin may influence cognitive and memory-related processes.

Despite the promising results indicating a significant improvement in delayed recall, the study acknowledges limitations, including the limited number of available studies, variations in administration methods, and potential sources of bias. The importance of replication studies, standardization of protocols, and further investigations into the underlying neural mechanisms is emphasized. The findings not only contribute to the current body of literature but also advocate for future research to unlock the full therapeutic potential of intranasal insulin in managing cognitive deficits and memory-related disorders.

Conclusions

Our findings yield compelling evidence affirming the significance and efficacy of intranasal insulin administration in augmenting delayed recall. The observed results manifest a noteworthy enhancement in delayed recall function, with no discernible impact on immediate recall. These findings have crucial implications for the potential therapeutic utilization of intranasal insulin in cognitive enhancement and memory-related disorders.

The affirmative outcomes of our study establish a robust foundation for future investigations in this domain. Subsequent studies employing consistent intranasal insulin approaches and employing uniform measurement scales are imperative to authenticate and build upon our findings.

Replication studies are essential for fortifying the evidentiary base and cultivating a more comprehensive comprehension of the cognitive benefits linked with intranasal insulin administration. Furthermore, forthcoming endeavors should concentrate on elucidating the underlying mechanisms by which intranasal insulin exerts its effects on delayed recall. Investigating the neural pathways and molecular processes involved in insulin-mediated memory enhancement will contribute to a profound understanding of the therapeutic potential of this intervention and its impact on distinct brain regions.

Additionally, standardizing protocols for assessing cognitive outcomes in studies involving intranasal insulin is imperative. The establishment of consistent measurement scales and methodologies will facilitate cross-study comparisons, fostering the accumulation of robust evidence substantiating the cognitive benefits of intranasal insulin.

In conclusion, our study augments the expanding body of evidence endorsing the potential benefits of intranasal insulin administration in enhancing delayed recall. Further research is warranted to explore the full therapeutic potential of this intervention and its applicability in managing memory-related disorders. It is noteworthy that the current results of intranasal insulin are encouraging concerning safety and efficacy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

Conceptualization, MD.G.G and I.C.R; methodology, A.S.L.; software, C.P.M.; validation, MD.G.G, I.C.R and A.S.L; formal analysis, C.A.B; investigation, MD.G.G; resources, MD.G.G.; data curation, I.C.R.; writing—original draft preparation, MD.G.G.; writ-ing—review and editing, MD.G.G, I.C.R and A.S.L.; visualization, I.M.G.; supervision, A.S.L.; project administration, I.C.R; funding acquisition, I.C.R. All authors have read and agreed to the published version of the manuscript.”

Declarations

Conflict of interest

No conflict of interest has been declared by the authors.