Abstract
A growing number of investigations are exploring the utility of intranasal insulin as a means of mitigating cognitive decline. However, as a basic tenant of dementia prevention programs is increasing physical activity, it is essential to obtain a preliminary assessment of the safety profile of combining intranasal insulin with physical activity; to ensure that undue risks are not incurred. Utilizing a randomized double-blind placebo-controlled design, a sample of 116 non-diabetic, fasted college-aged adults were randomly assigned to receive a dose of 0-to-120 IU of NovoLog (Insulin Aspart) before being randomized to 20 min of exercise or sitting control condition. The safety of intranasal insulin was assessed by examining the incidence of potential symptoms of hypoglycemia and changes in peripheral blood glucose. The efficacy of a combination therapeutic approach was assessed using behavioral measures of inhibition and sustained attention alongside neuroelectric indices of attentional engagement. The frequency of symptoms reported following administration of intranasal insulin were not observed to interact with exercise so as to make their occurrence any more or less prominent, nor was the frequency observed to relate to the dose of intranasal insulin. However, doses of intranasal insulin of 100 IU or more were observed to result in a 7-fold increase in the likelihood of a level 1 hypoglycemic event for those individuals in the exercise condition. This study provides preliminary evidence to suggest that exercise is not associated with an increase in risk when combined with lower doses of intranasal insulin.
Clinical trial registration The trial is registered at ClinicalTrials.gov, number NCT04292535.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11011-021-00727-2/MediaObjects/11011_2021_727_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11011-021-00727-2/MediaObjects/11011_2021_727_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11011-021-00727-2/MediaObjects/11011_2021_727_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11011-021-00727-2/MediaObjects/11011_2021_727_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11011-021-00727-2/MediaObjects/11011_2021_727_Fig5_HTML.png)
Similar content being viewed by others
Data availability
Data is available upon request.
References
Afrezza (2020) https://afrezza.com/
Bahar-Fuchs A, Clare L, Woods B (2013) Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer’s disease and vascular dementia. Cochrane Database Syst Rev 2013(6). https://doi.org/10.1002/14651858.CD003260.pub2
Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S (2010) Effects of Aerobic Exercise on Mild Cognitive Impairment: A Controlled Trial. Arch Neurol, 67(1). https://doi.org/10.1001/archneurol.2009.307
Bakirtzi K, Belfort G, Lopez-Coviella I, Kuruppu D, Cao L, Abel ED, Brownell A-L, Kandror KV (2009) Cerebellar neurons possess a vesicular compartment structurally and functionally similar to Glut4-storage vesicles from peripheral insulin-sensitive tissues. J Neurosci 29(16):5193–5201. https://doi.org/10.1523/JNEUROSCI.0858-09.2009
Baraniuk JN, Merck SJ (2008) Nasal reflexes: Implications for exercise, breathing, and sex. Curr Allergy Asthma Rep 8(2):147–153
Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10):1326–1334. https://doi.org/10.1016/j.psyneuen.2004.04.003
Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W (2006) Intranasal insulin improves memory in humans: Superiority of insulin aspart. Neuropsychopharmacology 32(1):239–243. https://doi.org/10.1038/sj.npp.1301193
Berger M, Halban PA, Muller WA, Offord RE, Renold AE, Vranic M (1978) Mobilization of subcutaneously injected tritiated insulin in rats: Effects of muscular exercise. Diabetologia 15(2):133–140
Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002) Sniffing neuropeptides: A transnasal approach to the human brain. Nat Neurosci 5(6):514–516. https://doi.org/10.1038/nn0602-849
Brooks GA, Fahey TD, Baldwin KM (2004) Exercise physiology: Human bioenergetics and its applications (fourth). McGraw-Hill, New York
Brünner YF, Kofoet A, Benedict C, Freiherr J (2015) Central insulin administration improves odor-cued reactivation of spatial memory in young men. J Clin Endocrinol Metab 100(1):212–219
Buchman AS, Boyle PA, Yu L, Shah RC, Wilson RS, Bennett DA (2012) Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 78(17):1323–1329
Carino GP, Mathiowitz E (1999) Oral insulin delivery. Adv Drug Deliv Rev 35(2–3):249–257
Chandler MC, McGowan AL, Payne BR, Hampton Wray A, Pontifex MB (2019) Aerobic fitness relates to differential attentional but not language-related cognitive processes. Brain Lang 198:104681. https://doi.org/10.1016/j.bandl.2019.104681
Chandler MC, McGowan AL, Ferguson DP, Pontifex MB (2020) Carbohydrate mouth rinse has no effects on behavioral or neuroelectric indices of cognition. Int J Psychophysiol. https://doi.org/10.1016/j.ijpsycho.2020.02.012
Chatrian GE, Lettich E, Nelson PL (1985) Ten percent electrode system for topographic studies of spontaneous and evoked EEG activity. American Journal of EEG Technology 25:83–92. https://doi.org/10.1080/00029238.1985.11080163
Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis 44(3):897–906. https://doi.org/10.3233/JAD-141791
Cooter S, Holt C (2011) Wonders of the Universe [Film]. BBC America
Craft S, 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 (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol 69(1):29–38. https://doi.org/10.1001/archneurol.2011.233
Craft S, Raman R, Chow TW, Rafii MS, Sun C-K, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS (2020) Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: A randomized clinical trial. JAMA Neurol 77(9):1099–1109. https://doi.org/10.1001/jamaneurol.2020.1840
Delorme A, Makeig S (2004) EEGLAB: An open source toolbox for analysis of single-trial EEG dynamics. J Neurosci Methods 134:9–21. https://doi.org/10.1016/j.jneumeth.2003.10.009
Eriksen CW, Eriksen BA (1974) Effects of noise letters upon the identification of a target letter in a non-search task. Percept Psychophys 25:249–263. https://doi.org/10.3758/BF03203267
Farina E, Fioravanti R, Chiavari L, Imbornone E, Alberoni M, Pomati S, Pinardi G, Pignatti R, Mariani C (2002) Comparing two programs of cognitive training in Alzheimer’s disease: A pilot study. Acta Neurol Scand 105(5):365–371
Galindo-Mendez B, Trevino JA, McGlinchey R, Fortier C, Lioutas V, Novak P, Mantzoros CS, Ngo L, Novak V (2020) Memory advancement by intranasal insulin in type 2 diabetes (MemAID) randomized controlled clinical trial: Design, methods and rationale. Contemp Clin Trials 89:105934. https://doi.org/10.1016/j.cct.2020.105934
Giroux M (2005) Controlled particle dispersion™: Effective nasal delivery from a versatile, flexible technology platform. ONdrugDelivery Ltd
Gramfort A, Luessi M, Larson E, Engemann DA, Strohmeier D, Brodbeck C, Goj R, Jas M, Brooks T, Parkkonen L, Hämäläinen M (2013) MEG and EEG data analysis with MNE-Python. Front Neurosci 7:1–13. https://doi.org/10.3389/fnins.2013.00267
Grossberg GT, Manes F, Allegri RF, Gutiérrez-Robledo LM, Gloger S, **e L, Jia XD, Pejović V, Miller ML, Perhach JL, Graham SM (2013) The safety, tolerability, and efficacy of once-daily memantine (28 mg): A multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs 27(6):469–478. https://doi.org/10.1007/s40263-013-0077-7
Heni M, Kullmann S, Preissl H, Fritsche A, Häring H-U (2015) Impaired insulin action in the human brain: Causes and metabolic consequences. Nat Rev Endocrinol 11(12):701
Hill JM, Lesniak MA, Pert CB, Roth J (1986) Autoradiographic localization of insulin receptors in rat brain: Prominence in olfactory and limbic areas. Neuroscience 17(4):1127–1138. https://doi.org/10.1016/0306-4522(86)90082-5
Hosseini S, Wei X, Wilkins JV Jr, Fergusson CP, Mohammadi R, Vorona G, Golshahi L (2019) In vitro measurement of regional nasal drug delivery with Flonase,® Flonase® SensimistTM and MAD NasalTM in anatomically correct nasal airway replicas of pediatric and adult human subjects. J Aerosol Med Pulm Drug Deliv 32(6):374–385
Hui DS, Chow BK, Chu LCY, Ng SS, Hall SD, Gin T, Chan MTV (2009) Exhaled air and aerosolized droplet dispersion during application of a jet nebulizer. Chest 135(3):648–654. https://doi.org/10.1378/chest.08-1998
In ’t Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MMB, Stricker BHC (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345(21), 1515–1521. https://doi.org/10.1056/NEJMoa010178
Intlekofer KA, Cotman CW (2013) Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Neurobiol Dis 57:47–55
Kern W, Born J, Schreiber H, Fehm HL (1999) Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 48(3):557–563
Kjøbsted R, Roll JLW, Jørgensen NO, Birk JB, Foretz M, Viollet B, Chadt A, Al-Hasani H, Wojtaszewski JF (2019) AMPK and TBC1D1 regulate muscle glucose uptake after, but not during, exercise and contraction. Diabetes 68(7):1427–1440. https://doi.org/10.2337/db19-0050
Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring H-U (2016) Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev 96(4):1169–1209. https://doi.org/10.1152/physrev.00032.2015
Lakens D (2013) Calculating and reporting effect sizes to facilitate cumulative science: A practical primer for t-tests and ANOVAs. Front Psychol 4(863):1–12. https://doi.org/10.3389/fpsyg.2013.00863
Matthews KA, Xu W, Gaglioti AH, Holt JB, Croft JB, Mack D, McGuire LC (2018) Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged ≥ 65 years. Alzheimers Dement 15(1):17–24. https://doi.org/10.1016/j.jalz.2018.06.3063
McGowan AL, Chandler MC, Brascamp JW, Pontifex MB (2019) Pupillometric indices of locus-coeruleus activation are not modulated following single bouts of exercise. Int J Psychophysiol 140:41–52. https://doi.org/10.1016/j.ijpsycho.2019.04.004
Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT (2015) MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement 11(9):1007–1014. https://doi.org/10.1016/j.jalz.2014.11.009
Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, Wilkins HM, Brooks WM, Billinger SA, Swerdlow RH, Burns JM (2017) Aerobic exercise for Alzheimer’s disease: A randomized controlled pilot trial. PLoS One 12(2). https://doi.org/10.1371/journal.pone.0170547
Neale C, Johnston P, Hughes M, Scholey A (2015) Functional activation during the rapid visual information processing task in a middle aged cohort: An fMRI study. PLoS One 10(10):e0138994. https://doi.org/10.1371/journal.pone.0138994
Novak V, Milberg W, Hao Y, Munshi M, Novak P, Galica A, Manor B, Roberson P, Craft S, Abduljalil A (2014) Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37(3):751–759. https://doi.org/10.2337/dc13-1672
Peirce JW (2009) Generating stimuli for neuroscience using PsychoPy. Fron Neuroinformatics 2:10. https://doi.org/10.3389/neuro.11.010.2008
Polich J (2007) Updating P300: An integrative theory of P3a and P3b. Clin Neurophysiol 118:2128–2148. https://doi.org/10.1016/j.clinph.2007.04.019
Pontifex MB, Parks AC, Henning DA, Kamijo K (2015) Single bouts of exercise selectively sustain attentional processes. Psychophysiology 52(5):618–625. https://doi.org/10.1111/psyp.12395
Pontifex MB, Gwizdala KL, Parks AC, Pfeiffer KA, Fenn KM (2016) The association between physical activity during the day and long-term memory stability. Sci Rep 6:38148. https://doi.org/10.1038/srep38148
Pontifex MB, Gwizdala KL, Parks AC, Billinger M, Brunner C (2017) Variability of ICA decomposition may impact EEG signals when used to remove eyeblink artifacts. Psychophysiology 54(3):386–398. https://doi.org/10.1111/psyp.12804
Pontifex MB, Miskovic V, Laszlo S (2017) Evaluating the efficacy of fully automated approaches for the selection of eyeblink ICA components. Psychophysiology 54(5):780–791. https://doi.org/10.1111/psyp.12827
Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype. Neurobiol Aging 27(3):451–458. https://doi.org/10.1016/j.neurobiolaging.2005.03.016
Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JCS, DeGroodt W, Mehta P, Craft S (2008) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70(6):440–448. https://doi.org/10.1212/01.WNL.0000265401.62434.36
Scarmeas N, Stern Y, Tang M-X, Mayeux R, Luchsinger JA (2006) Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 59(6):912–921. https://doi.org/10.1002/ana.20854
Schmid V, Kullmann S, Gfrörer W, Hund V, Hallschmid M, Lipp H-P, Häring H-U, Preissl H, Fritsche A, Heni M (2018) Safety of intranasal human insulin: A review. Diabetes Obes Metab 20(7):1563–1577. https://doi.org/10.1111/dom.13279
Shvartz E, Reibold RC (1990) Aerobic fitness norms for males and females aged 6 to 75 years: A review. Aviat Space Environ Med 61:3–11
Teleflex (2013) LMA® MAD NASAL™ Intranasal mucosal atomization device
Thomas S, Reading J, Shephard RJ (1992) Revision of the physical activity readiness questionnaire (PAR-Q). Can J Sport Sci 17:338–345
Tuominen JA, Karonen S-L, Melamies L, Bolli G, Koivisto VA (1995) Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue. Diabetologia 38(1):106–111
Unger JW, Livingston JN, Moss AM (1991) Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects. Prog Neurobiol 36(5):343–362. https://doi.org/10.1016/0301-0082(91)90015-S
Wechsler D (2011) Wechsler abbreviated scale of intelligence, 2nd ed. Pearson Assessments, Toronto
Yu F, Thomas W, Nelson NW, Bronas UG, Dysken M, Wyman JF (2015) Impact of 6-month aerobic exercise on Alzheimer’s symptoms. J Appl Gerontol 34(4):484–500. https://doi.org/10.1177/0733464813512895
Acknowledgements
Support for this investigation was provided by a Dissertation Completion Fellowship awarded to K. L. Gwizdala through the Department of Kinesiology at Michigan State University.
Author information
Authors and Affiliations
Contributions
Kathryn L. Gwizdala: Methodology, Formal Analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing, Visualization, Funding Acquisition. David P. Ferguson: Methodology, Writing – Review & Editing, Supervision, Project Administration. Jeffery Kovan: Methodology, Writing – Review & Editing, Supervision. Vera Novak: Methodology, Writing – Review & Editing. Matthew B. Pontifex: Methodology, Software, Validation, Formal Analysis, Data Curation, Writing – Original Draft, Visualization, Supervision, Project Administration, Funding Acquisition.
Corresponding author
Ethics declarations
Conflict of interest
No conflicting financial interests exist.
Ethical approval
All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This investigation was approved by the Michigan State University Human Research Protection Program.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The results of this manuscript have not been previously presented.
Rights and permissions
About this article
Cite this article
Gwizdala, K.L., Ferguson, D.P., Kovan, J. et al. Placebo controlled phase II clinical trial: Safety and efficacy of combining intranasal insulin & acute exercise. Metab Brain Dis 36, 1289–1303 (2021). https://doi.org/10.1007/s11011-021-00727-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-021-00727-2