I figured it would be cool to have a centralized location to collect all the recent and future research on intranasal insulin in humans.

So I made one!

I’ll keep adding studies as they come out since this treatment has the potential to radically transform a lot of people’s lives.

I’ve written about how to make it legally and affordably at home here and here.

I’ve been using it on and off for the past 6+ months and it’s one of the best cognitive enhancers I’ve ever tried.

I’ve only tried 500+ cognitive enhancers so I may not be the best person to ask. =)

Enjoy the beautiful science!

Human Studies on Intranasal Insulin

https://www.ncbi.nlm.nih.gov/pubmed/27577546

Eur J Hum Genet. 2016 Aug 31. doi: 10.1038/ejhg.2016.109. [Epub ahead of print]

Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.

Zwanenburg RJ1, Bocca G2, Ruiter SA3, Dillingh JH4, Flapper BC2, van den Heuvel ER5, van Ravenswaaij-Arts CM1.
Author information

Abstract
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.European Journal of Human Genetics advance online publication, 31 August 2016; doi:10.1038/ejhg.2016.109.

http://www.ncbi.nlm.nih.gov/pubmed/26275583

Rhinology. 2015 Dec;53(4):371-8. doi: 10.4193/Rhin15.065.

Intranasal insulin influences the olfactory performance of patients with smell loss, dependent on the body mass index: A pilot study.

Schöpf V, Kollndorfer K, Pollak M, Mueller CA, Freiherr J.

Abstract

BACKGROUND:
The application of intranasal insulin in healthy humans has been linked to improved memory function, reduced food intake, and increased olfactory thresholds. There has also been some correlation between the morbidities associated with central nervous system (CNS) insulin resistance, such as type II diabetes mellitus, Alzheimer’s disease, obesity, and impaired odour recognition. Given that impaired odour recognition is an important component of olfactory performance, mechanisms that govern these effects may account for impaired olfactory functions in anosmic patients.
METHODOLOGY:
Ten patients with post-infectious olfactory loss received intranasal administration of 40 IU insulin or a placebo solution, as well as olfactory performance tests before and after administration.
RESULTS:
When administered insulin, patients exhibited an immediate performance improvement with regard to olfactory sensitivity and olfactory intensity ratings. In addition, more odours were correctly identified. Furthermore, an improvement in the odour identification task was detected in patients with higher body mass index.
CONCLUSION:
Results of this pilot study shed light on the link between cerebral insulin level and an impaired sense of smell. This research line might provide a better understanding of olfactory loss in relation to eating and dietary behavior, and could offer opportunities to develop faster therapeutic intervention for patients with olfactory dysfunction.

http://www.ncbi.nlm.nih.gov/pubmed/25374101

J Alzheimers Dis. 2015;44(3):897-906. doi: 10.3233/JAD-141791.

Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia.

Claxton A1, Baker LD2, Hanson A1, Trittschuh EH1, Cholerton B3, Morgan A1, Callaghan M1, Arbuckle M4, Behl C1, Craft S2.
Author information

Abstract
Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer’s disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.

http://www.ncbi.nlm.nih.gov/pubmed/25795413

Diabetes Care. 2015 Jun;38(6):1044-50. doi: 10.2337/dc14-2319. Epub 2015 Mar 20.

Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults.

Kullmann S1, Heni M2, Veit R3, Scheffler K4, Machann J5, Häring HU2, Fritsche A2, Preissl H5.
Author information

Abstract
OBJECTIVE:
Impaired brain insulin action has been linked to obesity, type 2 diabetes, and neurodegenerative diseases. To date, the central nervous effects of insulin in obese humans still remain ill defined, and no study thus far has evaluated the specific brain areas affected by insulin resistance.
RESEARCH DESIGN AND METHODS:
In 25 healthy lean and 23 overweight/obese participants, we performed magnetic resonance imaging to measure cerebral blood flow (CBF) before and 15 and 30 min after application of intranasal insulin or placebo. Additionally, participants explicitly rated pictures of high-caloric savory and sweet food 60 min after the spray for wanting and liking.
RESULTS:
In response to insulin compared with placebo, we found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, we observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures such as disinhibition and food craving. Behaviorally, we were able to observe a significant reduction for the wanting of sweet foods after insulin application in lean men only.
CONCLUSIONS:
Brain insulin action was selectively impaired in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue, potentially promoting an altered homeostatic set point and reduced inhibitory control contributing to overeating behavior.

http://www.ncbi.nlm.nih.gov/pubmed/25288674

Diabetes. 2015 Mar;64(3):766-74. doi: 10.2337/db14-0685. Epub 2014 Oct 6.

Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations.

Dash S1, Xiao C1, Morgantini C1, Koulajian K1, Lewis GF2.
Author information

Abstract
Intranasal insulin (INI) has been shown to modulate food intake and food-related activity in the central nervous system in humans. Because INI increases insulin concentration in the cerebrospinal fluid, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies, but whether it regulates endogenous glucose production (EGP) is not known. To assess the role of INI in the regulation of EGP, eight healthy men were studied in a single-blind, crossover study with two randomized visits (one with 40 IU INI and the other with intranasal placebo [INP] administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia. Between 180 and 360 min after administration, INI significantly suppressed EGP by 35.6% compared with INP, despite similar venous insulin concentrations. In conclusion, INI lowers EGP in humans compared with INP, despite similar venous insulin concentrations. INI may therefore be of value in treating excess liver glucose production in diabetes.

http://www.ncbi.nlm.nih.gov/pubmed/25249577

Diabetes. 2015 Mar;64(3):1025-34. doi: 10.2337/db14-1000. Epub 2014 Sep 23.

Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes.

Zhang H1, Hao Y1, Manor B2, Novak P3, Milberg W4, Zhang J5, Fang J5, Novak V6.
Author information

Abstract
Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.

http://www.ncbi.nlm.nih.gov/pubmed/25337926

J Clin Endocrinol Metab. 2015 Jan;100(1):212-9. doi: 10.1210/jc.2014-3018.

Central insulin administration improves odor-cued reactivation of spatial memory in young men.

Brünner YF1, Kofoet A, Benedict C, Freiherr J.
Author information

Abstract
CONTEXT:
Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing.
OBJECTIVE:
The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men.
DESIGN:
We applied a double-blind, placebo-controlled, counterbalanced within-subject design.
SETTING:
The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled ∼10 min later (without feedback). To test if insulin’s putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task.
RESULTS:
Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment.
CONCLUSIONS:
These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

http://www.ncbi.nlm.nih.gov/pubmed/25265284

Psychoneuroendocrinology. 2014 Dec;50:311-20. doi: 10.1016/j.psyneuen.2014.09.006. Epub 2014 Sep 16.

Cortisol, but not intranasal insulin, affects the central processing of visual food cues.

Ferreira de Sá DS1, Schulz A2, Streit FE3, Turner JD4, Oitzl MS5, Blumenthal TD6, Schächinger H3.
Author information

Abstract
Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of “high glycemic” food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the “frustrative nonreward” model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.

http://www.ncbi.nlm.nih.gov/pubmed/25028522

Diabetes. 2014 Dec;63(12):4083-8. doi: 10.2337/db14-0477. Epub 2014 Jul 15.

Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men.

Heni M1, Wagner R2, Kullmann S3, Veit R4, Mat Husin H5, Linder K1, Benkendorff C6, Peter A1, Stefan N1, Häring HU1, Preissl H3, Fritsche A1.
Author information

Abstract
Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on whole-body insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

http://www.ncbi.nlm.nih.gov/pubmed/23907764

Hum Brain Mapp. 2014 May;35(5):1944-56. doi: 10.1002/hbm.22304. Epub 2013 Aug 1.

Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation.

Schilling TM1, Ferreira de Sá DS, Westerhausen R, Strelzyk F, Larra MF, Hallschmid M, Savaskan E, Oitzl MS, Busch HP, Naumann E, Schächinger H.
Author information

Abstract
Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior.

http://www.ncbi.nlm.nih.gov/pubmed/23839870

Obesity (Silver Spring). 2014 Mar;22(3):925-31. doi: 10.1002/oby.20573. Epub 2014 Jan 25.

Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

Ketterer C1, Heni M, Stingl K, Tschritter O, Linder K, Wagner R, Machicao F, Häring HU, Preissl H, Staiger H, Fritsche A.
Author information

Abstract
OBJECTIVE:
The cannabinoid-receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2, encoding the cannabinoid-receptor 2, are associated with weight in a cross-sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action.
METHODS:
2006 subjects at increased risk for type 2 diabetes mellitus were genotyped for 5 tagging SNPs in the CNR2 locus. All subjects underwent a 75-g OGTT. 345 subjects participated in a lifestyle intervention (TUebingen Lifestyle Intervention Programme). Cerebrocortical insulin sensitivity was measured by magnetoencephalography after intranasal insulin application in 43 subjects.
RESULTS:
In the cross-sectional cohort, the minor allele of rs3123554 was associated with lower BMI (Padd = 0.01, Prec = 0.004), and this was attributable to its effect in women only. Interestingly, during lifestyle intervention, carriers of the same allele lost less body weight (Padd = 0.03, Prec = 0.008). Moreover, carriers of this minor allele showed lower cerebral insulin sensitivity (Prec = 0.0402).
CONCLUSIONS:
The minor allele of rs3123554 is associated cross-sectionally with lower body weight, whereas during intervention the same allele led to less reduction of body weight. Reduced cerebral insulin sensitivity in carriers of this allele might contribute to these disadvantageous effects during lifestyle intervention.

http://www.ncbi.nlm.nih.gov/pubmed/24423295

J Clin Endocrinol Metab. 2014 Feb;99(2):E246-51. doi: 10.1210/jc.2013-3169. Epub 2013 Jan 1.

Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans.

Iwen KA1, Scherer T, Heni M, Sayk F, Wellnitz T, Machleidt F, Preissl H, Häring HU, Fritsche A, Lehnert H, Buettner C, Hallschmid M.
Author information

Abstract
CONTEXT:
Insulin infused into the central nervous system of rats suppresses lipolysis in white adipose tissue, indicating a role of brain insulin in regulating systemic lipid metabolism.
OBJECTIVE:
We investigated whether central nervous insulin delivery suppresses lipolysis in healthy humans.
DESIGN:
Placebo-controlled, balanced within-subject comparisons were performed in both a main and an independent corroborative experiment. SETTING/PARTICIPANTS/INTERVENTION: Two groups of healthy volunteers were examined at the German University Clinics of Lübeck and Tübingen, respectively, with molecular analyses taking place at Mt Sinai School of Medicine (New York, New York). The 14 healthy male subjects of the main study and the 22 women and 5 men of the corroborative study each received 160 IU of human insulin intranasally.
MAIN OUTCOME MEASURES:
In the main study, we measured systemic levels of free fatty acids (FFAs), triglycerides, and glycerol and the rate of appearance of deuterated glycerol as an estimate of lipolysis before and after intranasal insulin administration. We also analyzed the expression of key lipolytic enzymes in sc fat biopsies and measured blood glucose and glucoregulatory hormones. In the corroborative study, FFA concentrations were assessed before and after intranasal insulin administration.
RESULTS:
In the main experiment, intranasal insulin suppressed circulating FFA concentrations and lipolysis (rate of appearance of deuterated glycerol) in the absence of significant changes in circulating insulin levels. Lipolytic protein expression in sc adipose tissue was not affected. The corroborative study confirmed that intranasal insulin lowers systemic FFA concentrations.
CONCLUSIONS:
Our findings indicate that brain insulin controls systemic lipolysis in healthy humans by predominantly acting on non-sc adipose tissue.

http://www.ncbi.nlm.nih.gov/pubmed/24101698

Diabetes Care. 2014;37(3):751-9. doi: 10.2337/dc13-1672. Epub 2013 Oct 7.

Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes.

Novak V1, Milberg W, Hao Y, Munshi M, Novak P, Galica A, Manor B, Roberson P, Craft S, Abduljalil A.
Author information

Abstract
OBJECTIVE:
To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM).
RESEARCH DESIGN AND METHODS:
This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation.
RESULTS:
Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R(2)adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R(2)adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory.
CONCLUSIONS:
Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23507773

J Alzheimers Dis. 2013;35(4):789-97. doi: 10.3233/JAD-122308.

Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease.

Claxton A1, Baker LD, Wilkinson CW, Trittschuh EH, Chapman D, Watson GS, Cholerton B, Plymate SR, Arbuckle M, Craft S.
Author information

Abstract
A previous clinical trial demonstrated that four months of treatment with intranasal insulin improves cognition and function for patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI), but prior studies suggest that response to insulin treatment may differ by sex and ApoE ε4 carriage. Thus, responder analyses using repeated measures analysis of covariance were completed on the trial’s 104 participants with MCI or AD who received either placebo or 20 or 40 IU of insulin for 4 months, administered by a nasal delivery device. Results indicate that men and women with memory impairment responded differently to intranasal insulin treatment. On delayed story memory, men and women showed cognitive improvement when taking 20 IU of intranasal insulin, but only men showed cognitive improvement for the 40 IU dose. The sex difference was most apparent for ApoE ε4 negative individuals. For the 40 IU dose, ApoE ε4 negative men improved while ApoE ε4 negative women worsened. Their ApoE ε4 positive counterparts remained cognitively stable. This sex effect was not detected in functional measures. However, functional abilities were relatively preserved for women on either dose of intranasal insulin compared with men. Unlike previous studies with young adults, neither men nor women taking intranasal insulin exhibited a significant change in weight over 4 months of treatment.

http://www.ncbi.nlm.nih.gov/pubmed/23928664

J Clin Endocrinol Metab. 2013 Oct;98(10):E1626-30. doi: 10.1210/jc.2013-2061. Epub 2013 Aug 8.

Intranasal insulin reduces olfactory sensitivity in normosmic humans.

Brünner YF1, Benedict C, Freiherr J.
Author information

Abstract
CONTEXT:
High densities of insulin receptors are found throughout the human brain, including the olfactory bulb, an essential brain area for odor processing. This brain region is the phylogenetically oldest part of the olfactory central nervous system.
OBJECTIVE:
We hypothesized that enhanced brain insulin signaling would modulate olfactory processing in humans.
DESIGN:
We applied a double-blind, placebo-controlled, balanced within-subject design.
SETTING:
This study was conducted in the research unit of a university hospital. INTERVENTIONS/PARTICIPANTS/MAIN OUTCOME MEASURES: A single dose of either insulin (40 IU) or placebo was intranasally administered to 17 normal-weight normosmic participants (7 women). Subjects’ olfactory abilities were examined by means of an olfactory threshold test (odorant n-butanol) and an olfactory discrimination test. In addition, circulating concentrations of glucose, insulin, and cortisol levels were measured.
RESULTS:
After intranasal insulin administration, subjects’ sensitivity for the odorant n-butanol was significantly decreased compared with that for the placebo condition (-13%; P = .025), whereas olfactory discrimination ability was not (P = .841). While serum insulin and serum cortisol were not altered after intranasal insulin administration, there was a small but significant drop in plasma glucose levels. Importantly, a correlational analysis demonstrated that this treatment-induced drop in plasma glucose was not related to the effects of intranasal insulin on olfactory sensitivity.
CONCLUSIONS:
These findings suggest that intranasal insulin impairs olfactory sensitivity for a nonfood odorant, whereas no such effects were found for olfactory discrimination. Thus, variations in brain insulin signaling most likely have implications for the olfactory threshold of normosmic humans. Bearing in mind the fact that insulin acts as an anorexigenic signal in the human brain, further studies are needed to test whether intranasal insulin also impairs the ability of humans to perceive food-related odors.

http://www.ncbi.nlm.nih.gov/pubmed/23434504

Schizophr Res. 2013 May;146(1-3):40-5. doi: 10.1016/j.schres.2013.01.034. Epub 2013 Feb 21.

No effect of adjunctive, repeated dose intranasal insulin treatment on body metabolism in patients with schizophrenia.

Li J1, Li X, Liu E, Copeland P, Freudenreich O, Goff DC, Henderson DC, Song X, Fan X.
Author information

Abstract
OBJECTIVE:
This study examined the effect of adjunctive intranasal insulin therapy on body metabolism in patients with schizophrenia.
METHOD:
Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and had been on stable dose of antipsychotic agent for at least one month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. The whole body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline, and repeated at week 8.
RESULTS:
A total number of 39 subjects completed the study (18 in the insulin group, 21 in the placebo group). There were no significant differences between the two groups in week 8 changes for body weight, body mass index, waist circumference, as well as various measures of lipid particles (p’s>0.100). The DXA assessment showed no significant differences between the two groups in week 8 changes for fat mass, lean mass or total mass (p’s>0.100).
CONCLUSION:
In the present study, adjunctive therapy of intranasal insulin did not seem to improve body metabolism in patients with schizophrenia. The implications for future studies were discussed.

http://www.ncbi.nlm.nih.gov/pubmed/22922661

Neuroendocrinology. 2013;97(2):176-82. doi: 10.1159/000341406. Epub 2012 Aug 25.

Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women.

Kullmann S1, Frank S, Heni M, Ketterer C, Veit R, Häring HU, Fritsche A, Preissl H.
Author information

Abstract
AIM:
There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain’s non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application.
METHODS:
We performed ‘resting-state’ functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin.
RESULTS:
Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index.
CONCLUSION:
This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23107220

Bipolar Disord. 2012 Nov;14(7):697-706. doi: 10.1111/bdi.12006.

A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder.

McIntyre RS1, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, Macqueen G, Lewis GF, Kennedy SH.
Author information

Abstract
BACKGROUND:
Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder.
METHODS:
Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and ≤ 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery.
RESULTS:
There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns.
CONCLUSIONS:
Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre-existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup.

http://www.ncbi.nlm.nih.gov/pubmed/22586589

Diabetes. 2012 Sep;61(9):2261-8. doi: 10.2337/db12-0025. Epub 2012 May 14.

Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans.

Jauch-Chara K1, Friedrich A, Rezmer M, Melchert UH, G Scholand-Engler H, Hallschmid M, Oltmanns KM.
Author information

Abstract
Cerebral insulin exerts anorexic effects in humans and animals. The underlying mechanisms, however, are not clear. Because insulin physiologically facilitates glucose uptake by most tissues of the body and thereby fosters intracellular energy supply, we hypothesized that intranasal insulin reduces food consumption via enhancement of the neuroenergetic level. In a double-blind, placebo-controlled, within-subject comparison, 15 healthy men (BMI 22.2 ± 0.37 kg/m(2)) aged 22-28 years were intranasally administered insulin (40 IU) or placebo after an overnight fast. Cerebral energy metabolism was assessed by (31)P magnetic resonance spectroscopy. At 100 min after spray administration, participants consumed ad libitum from a test buffet. Our data show that intranasal insulin increases brain energy (i.e., adenosine triphosphate and phosphocreatine levels). Cerebral energy content correlates inversely with subsequent calorie intake in the control condition. Moreover, the neuroenergetic rise upon insulin administration correlates with the consecutive reduction in free-choice calorie consumption. Brain energy levels may therefore constitute a predictive value for food intake. Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising option in this regard.

https://www.ncbi.nlm.nih.gov/pubmed/26855666

Aging health. 2012;8(1):61-64.

Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics.

de la Monte SM1.
Author information

Abstract
Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12. Alzheimer’s disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer’s, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimer’s and mild cognitive impairment, i.e. the precursor to Alzheimer’s. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimer’s disease.

http://www.ncbi.nlm.nih.gov/pubmed/21911655

Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.

Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.

Craft S1, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B.
Author information

Abstract
OBJECTIVE:
To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).
DESIGN:
Randomized, double-blind, placebo-controlled trial.
SETTING:
Clinical research unit of a Veterans Affairs medical center.
PARTICIPANTS:
The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).
MAIN OUTCOME MEASURES:
Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease’s Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.
RESULTS:
Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. CONCLUSIONS: These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD.

http://www.ncbi.nlm.nih.gov/pubmed/21694461

J Alzheimers Dis. 2011;26(3):477-84. doi: 10.3233/JAD-2011-110149.

A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease.

Stein MS1, Scherer SC, Ladd KS, Harrison LC.
Author information
1Royal Melbourne Hospital, Parkville, VIC, Australia Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. mark.stein@mh.org.au

Abstract
Poor vitamin D nutrition is linked with dementia, but vitamin D has not been tested in a randomized controlled trial (RCT) in Alzheimer’s disease (AD). Nasal insulin acutely improves cognition and vitamin D upregulates insulin receptor expression and enhances insulin action. In an RCT we examined the effect of high-dose vitamin D followed by nasal insulin on memory and disability in mild-moderate AD. 63 community-dwelling individuals aged > 60 were recruited; 32 with mild-moderate disease (Folstein Mini-Mental State Examination [MMSE] score 12-24) met entry criteria and were randomized. All took low-dose vitamin D (1000 IU/day) throughout. After run-in (8 weeks), they were randomized to additional high-dose D/placebo for 8 weeks, followed immediately by randomization to nasal insulin (60 IU qid)/placebo for 48 h. Primary outcome measures were Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) and Disability Assessment in Dementia (after high-dose D) and ADAS-cog and Wechsler Memory Scale-Revised Logical memory (WMS-R LM) for immediate and delayed recall (after nasal insulin). Baseline median (interquartile range, IR) age, MMSE, and ADAS-cog were 77.5 (69-80), 19.5 (17-22), and 25.5 (20-31), respectively. Median 25OHD increased from 49 to 60 nM (p < 0.01) after run-in and was 187 nM after high-dose vitamin D and 72 nM after placebo (p < 0.001). Neither cognition nor disability changed significantly after high-dose D. ADAS-cog improved by a median (IR) of 9 (1-11) with nasal insulin after placebo high-dose vitamin D (p = 0.02), but may represent regression to the mean as WLS-R LM did not change. We conclude that high-dose vitamin D provides no benefit for cognition or disability over low-dose vitamin D in mild-moderate AD.

http://www.ncbi.nlm.nih.gov/pubmed/21461638

Diabetologia. 2011 Jun;54(6):1502-6. doi: 10.1007/s00125-011-2111-y. Epub 2011 Apr 2.

Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial.

Stockhorst U1, de Fries D, Steingrueber HJ, Scherbaum WA.
Author information

Abstract
AIMS/HYPOTHESIS:
In humans, the intranasal route allows insulin to reach the brain while maintaining peripheral euglycaemia. Our aims were to examine acute (unconditioned) effects of central insulin on normal-range blood glucose and hormones in men, and to find out whether the effects of intranasal insulin can be learnt via classical conditioning.
METHODS:
In a randomised controlled trial, 32 healthy normal-weight men (mean age 24.2 [SEM 0.5], mean BMI 22.4 [0.3]) received a conditioned stimulus (CS) and six administrations of either soluble H-insulin 100 (20 U [0.2 ml]; group 1; n = 16) or vehicle (0.2 ml; group 2; n = 16) on day 1. The CS was the tarry smell of meta-cresol (used as a stabilising vehicle in many insulin preparations and placebos). On day 2, all participants received the CS and six administrations of placebo. Participants and experimenters were blinded to group assignment. Sixteen individuals were randomised to and analysed in each group. Participants were sequentially numbered for group allocation. The main outcome measures were blood glucose and insulin, expressed as cumulative difference-from-baseline changes.
RESULTS:
While maintaining euglycaemia, intranasal insulin induced an increase of peripheral insulin on day 1 (group 1, 17.78 [21.88] pmol/l vs group 2, -10.24 [9.42] pmol/l), and also on day 2 when the CS was given with placebo (group 1, 12.53 [5.57] pmol/l vs group 2, -5.51 [6.16] pmol/l). Moreover, a moderate reduction of blood glucose on day 1 (group 1, -0.54 [0.36] mmol/l vs group 2, 0.58 [0.48] mmol/l) was obtained (all p values <0.05). There were no adverse side effects. CONCLUSIONS/INTERPRETATION: The unconditioned blood glucose decrease on day 1 and the unconditioned and conditioned increases of peripheral insulin are indicative of brain-pancreas cross-talk. The conditionability of the hormonal responses reveals new applications for intranasal insulin.

https://www.ncbi.nlm.nih.gov/pubmed/20719831/

J Clin Endocrinol Metab. 2010 Dec;95(12):E468-72. doi: 10.1210/jc.2010-0744. Epub 2010 Aug 18.

Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory.

Krug R1, Benedict C, Born J, Hallschmid M.
Author information

Abstract

CONTEXT:
We have previously shown that enhancing brain insulin signaling by intranasal administration of a single dose of the hormone acutely reduces food intake in young men but not women, whereas its improving effects on spatial and working memory are restricted to young women.

OBJECTIVE:
Against the background of animal studies suggesting that low estrogen concentrations are a prerequisite for the anorexigenic impact of central nervous insulin, we extended our foregoing study by assessing intranasal insulin effects in postmenopausal women with comparatively low estrogen concentrations, expecting them to be more sensitive than young women to the anorexigenic effects of the hormone.

DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION:
In a within-subject, double-blind comparison performed at the University of Lübeck, 14 healthy postmenopausal women (body mass index, 23.71±0.6 kg/m2; age, 57.61±1.14 yr) were intranasally administered 160 IU regular human insulin or vehicle.

MAIN OUTCOME MEASURES:
Subjects performed a working memory task (digit span) and a hippocampus-dependent visuospatial memory task. Subsequently, free-choice food intake from an ad libitum breakfast buffet was measured.

RESULTS:
Contrary to expectations, results in postmenopausal women mirrored those found in young women (22.44±0.63 yr), i.e. insulin administration did not affect food intake (P>0.46), but did enhance performance in the prefrontal cortex-dependent working memory task (P<0.05). CONCLUSIONS: Low estrogen levels as present in postmenopausal women do not modulate the effects of intranasal insulin in females, suggesting that in humans as opposed to rats, estrogen signaling does not critically alter central nervous system sensitivity to the effects of insulin on energy homeostasis and cognition.

https://www.ncbi.nlm.nih.gov/pubmed/18948358

J Med Genet. 2009 Apr;46(4):217-22. doi: 10.1136/jmg.2008.062141. Epub 2008 Oct 23.

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.

Schmidt H1, Kern W, Giese R, Hallschmid M, Enders A.
Author information

Abstract

BACKGROUND:
The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease.

AIMS:
To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome.

METHODS:
We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed.

RESULTS:
The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding.

CONCLUSIONS:
We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.

http://www.ncbi.nlm.nih.gov/pubmed/18430999

J Alzheimers Dis. 2008 Apr;13(3):323-31.

Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.

Reger MA1, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S.
Author information

Abstract
Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer’s disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

https://www.ncbi.nlm.nih.gov/pubmed/17942819

Neurology. 2008 Feb 5;70(6):440-8. Epub 2007 Oct 17.

Intranasal insulin improves cognition and modulates beta-amyloid in early AD.

Reger MA1, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S.
Author information

Abstract

BACKGROUND:
Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes.

OBJECTIVE:
We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol.

METHODS:
Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment.

RESULTS:
Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207).

CONCLUSIONS:
The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

https://www.ncbi.nlm.nih.gov/pubmed/17848936

Int J Obes (Lond). 2008 Feb;32(2):275-82. Epub 2007 Sep 11.

Obese men respond to cognitive but not to catabolic brain insulin signaling.

Hallschmid M1, Benedict C, Schultes B, Born J, Kern W.
Author information

Abstract

CONTEXT AND OBJECTIVE:
Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound.

DESIGN, SUBJECTS AND MEASUREMENTS:
Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day(-1)) over 8 weeks to two groups of 15 obese men each.

RESULTS:
Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P>0.50) and body fat (P>0.44) in the obese subjects. However, in accordance with the effects in normal-weight men, declarative memory and mood were improved (P<0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (P<0.01) and cortisol levels (P<0.04) was reduced. CONCLUSIONS: Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.

https://www.ncbi.nlm.nih.gov/pubmed/16936707

Neuropsychopharmacology. 2007 Jan;32(1):239-43. Epub 2006 Aug 16.

Intranasal insulin improves memory in humans: superiority of insulin aspart.

Benedict C1, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W.
Author information

Abstract
There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and long-term (4 x 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (p<0.01) and the RH-I groups (p<0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (p<0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pubmed/15964100

Neurobiol Aging. 2006 Mar;27(3):451-8. Epub 2005 Jun 16.

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

Reger MA1, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S.
Author information

Abstract
Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer’s disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/16154436

Metabolism. 2005 Oct;54(10):1356-61.

Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings.

Benedict C1, Dodt C, Hallschmid M, Lepiorz M, Fehm HL, Born J, Kern W.
Author information

Abstract
Intranasal administration of insulin has been shown to influence neuroendocrine functions via an effect on central nervous mechanisms. Because insulin, in particular when infused into cerebral arteries, induces blood pressure (BP) elevation by an unknown mechanism, we investigated whether insulin exerts similar effects on BP after intranasal administration. To evaluate the immediate effects of insulin on BP, 20 IU of human insulin was intranasally administered every 10 minutes over a 2-hour period. Blood pressure, heart rate, and muscular sympathetic nervous activity (MSNA) were continuously monitored. For evaluating the effects of subchronic administration of insulin, changes during and after 8 weeks of treatment with 160 IU insulin/d on BP were monitored. Compared with placebo, the immediate nasal administration of insulin raised diastolic BP (12.21% +/- 5.10%; P < .05), mean arterial BP (10.81% +/- 4.32%; P < .04), and systolic BP (9.53% +/- 4.66%; P < .08), whereas MSNA and heart rate were unaffected. In contrast, prolonged intranasal insulin administration did not affect BP (P > .62 for all comparisons). The immediate increase in BP in the face of an unsuppressed MSNA after insulin suggests that intranasal insulin transiently changes the baroreflex set point. Thus, data suggest that intranasal insulin administration affects BP regulatory centers in the brain. However, the effect is not observed with prolonged administration of the hormone, suggesting the emergence of counterregulatory processes.

https://www.ncbi.nlm.nih.gov/pubmed/15288712

Psychoneuroendocrinology. 2004 Nov;29(10):1326-34.

Intranasal insulin improves memory in humans.

Benedict C1, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W.
Author information

Abstract
Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pubmed/15504987

Diabetes. 2004 Nov;53(11):3024-9.

Intranasal insulin reduces body fat in men but not in women.

Hallschmid M1, Benedict C, Schultes B, Fehm HL, Born J, Kern W.
Author information

Abstract

Insulin acts in the central nervous system to reduce food intake and body weight and is considered a major adiposity signal. After intranasal administration, insulin enters the cerebrospinal fluid compartment and alters brain functions in the absence of substantial absorption into the blood stream. Here we report the effects of 8 weeks of intranasal administration of insulin (4 x 40 IU/day) or placebo to two groups of healthy human subjects (12 men and 8 women in each group). The insulin-treated men lost 1.28 kg body wt and 1.38 kg of body fat, and their waist circumference decreased by 1.63 cm. Plasma leptin levels dropped by an average of 27%. In contrast, the insulin-treated women did not lose body fat and gained 1.04 kg body wt due to a rise in extracellular water. Our results provide a strong, first confirmation in humans that insulin acts as a negative feedback signal in the regulation of adiposity and point to a differential sensitivity to the catabolic effects of insulin based on sex.

https://www.ncbi.nlm.nih.gov/pubmed/12951650

Diabetes Metab Res Rev. 2003 Sep-Oct;19(5):415-20.

Intranasally administered insulin intended for prevention of type 1 diabetes–a safety study in healthy adults.

Kupila A1, Sipilä J, Keskinen P, Simell T, Knip M, Pulkki K, Simell O.
Author information

Abstract

BACKGROUND:
Intranasally applied insulin is one of the antigen-specific therapies currently tested in clinical type 1 diabetes prevention trials, for example, in the Type 1 Diabetes Prediction and Prevention Study (DIPP). The possibility that the therapy may cause hypoglycaemia or local irritation and the poorly known immunological safety of mucosal application of the antigen in healthy subjects prompted this study.

METHODS:
We used a randomised, placebo-controlled, double-blinded crossover study design with 3-week treatment periods to study the effects of once-daily intranasal application of human short-acting insulin without absorption-enhancing adjuvants in 20 non-diabetic adults. The selected 60 IU dose of insulin was equivalent to the weight-based dose used for the DIPP children. We investigated self-monitored blood glucose concentrations, nasal insulin effects and induction of diabetes-associated autoantibodies.

RESULTS:
The two treatment periods showed no differences in blood glucose concentrations or in the frequency of blood glucose values higher than 3.0 mmol/L. Of the eight measured hypoglycaemic values, only one, which occurred during placebo therapy, was associated with symptoms. Rhinoscopy revealed no nasal irritation, and mucociliary clearance, nasal airway patency and nasal airflow resistance were not affected by the insulin therapy. Eleven subjects complained of transient nasal stinging or unpleasant odour and one subject reduced the dose because of nasal irritation. The treatment did not induce production of any of the four diabetes-associated autoantibodies.

CONCLUSIONS:
Short-term use of intranasal insulin without absorption enhancers was predominantly well tolerated, the risk of hypoglycaemia was minimal and no objective nasal adverse effects were detected.

http://www.ncbi.nlm.nih.gov/pubmed/10078556

Diabetes. 1999 Mar;48(3):557-63.

Central nervous system effects of intranasally administered insulin during euglycemia in men.

Kern W1, Born J, Schreiber H, Fehm HL.
Author information

Abstract
Insulin receptors have been detected in several structures of the brain, yet the biological significance of insulin acting on the brain remains rather unclear. In humans, direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels. Since several intranasally administered viruses, peptides, and hormones have been shown to penetrate directly from the nose to the brain, we tested whether insulin after intranasal administration likewise has access to the brain. After a 60-min baseline period, insulin (20 IU H-Insulin 100 Hoechst) or vehicle (2.7 mg/ml m-Cresol) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design. Auditory-evoked potentials (AEP) indexing cortical sensory processing were recorded while the subjects performed a vigilance task (oddball paradigm) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo. Blood glucose and serum insulin levels were not affected by intranasal insulin. Compared with placebo, intranasal administration of insulin reduced amplitudes of the N1 (P < 0.005) and P3 (P < 0.02) components of the AEP and increased P3 latency (P < 0.05). The reduction in P3 amplitude was most pronounced over the frontal recording site (2.42 +/- 1.00 vs. 4.92 +/- 0.79 microV, P < 0.0005). At this site, after insulin administration, a broad negative shift developed in the AEP between 280 and 500 ms poststimulus (area under the curve -166.0 +/- 183.8 vs. 270.8 +/- 138.7 microV x ms after placebo, P < 0.01). The results suggest that after intranasal administration, insulin directly enters the brain and exerts distinct influences on central nervous functions in humans.