Intranasal insulin attenuates the hypothalamic–pituitary–adrenal axis response to psychosocial stress
Abstract
Previous studies have shown that intranasally administered insulin exerts an inhibitory influence on the basal hypothalamic-pituitary-adrenal (HPA) axis activity. To date, however, it remains unclear as to whether intranasal insulin does furthermore affect HPA axis responsiveness in situations of stress. Here, we tested whether intranasally administered insulin attenuates the HPA axis response to psychosocial stress. Fifty minutes before being exposed to the Trier Social Stress Test (TSST), 26 healthy young male participants received a single intranasal dose of human insulin (40 I.U.) or placebo in a placebo controlled, double-blind between-subject design. Plasma cortisol, saliva cortisol, heart rate, and blood pressure were measured at resting baseline and in response to the TSST. Plasma cortisol (P<.001) and saliva cortisol (P<.001) increased in response to stress, as did heart rate (P<.001) and blood pressure (P<.001). Intranasal insulin did not influence plasma or saliva cortisol, heart rate, blood pressure, blood glucose, and plasma insulin levels at baseline. However, intranasal insulin diminished the saliva cortisol (two-way ANOVA; treatment by time interaction: P=.05) and plasma cortisol (two-way ANOVA; treatment by time interaction: P=.05) response to the TSST without affecting heart rate, and blood pressure stress reactivity. Our data show that a single intranasal insulin administration effectively lowers stress-induced HPA axis responsiveness. Intranasal insulin may offer a therapeutic potential to prevent hyperactivity of the HPA system.
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Acute IN insulin administration of 40 IU to healthy young men reduced the increase in saliva and plasma cortisol during a psychosocial stress test.
“Acute IN insulin administration (40 IU) to healthy young men reduced the increase in saliva, as well as plasma cortisol, during a psychosocial stress test.”
From Intranasal insulin (2021) · cites this paper as [95]
Cites
Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.1.0389 · Cited by 7,541 · see citing works
Sapolsky, R. M. (2000) · Endocrine Reviews · doi:10.1210/er.21.1.55 · Cited by 7,533 · see citing works
Kirschbaum, C., Pirke, K.-M., & Hellhammer, D. H. (2008) · Neuropsychobiology · doi:10.1159/000119004 · Cited by 6,093 · see citing works
Dickerson, S. S., & Kemeny, M. E. (2004) · Psychological Bulletin · doi:10.1037/0033-2909.130.3.355 · Cited by 5,881 · see citing works
Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D. H. (2003) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(02)00108-7 · Cited by 3,638 · see citing works
Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis
Herman, J. P., & Cullinan, W. E. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10069-2 · Cited by 2,270 · see citing works
Kirschbaum, C., Kudielka, B. M., Gaab, J., Schommer, N. C., & Hellhammer, D. H. (1999) · Psychosomatic Medicine · doi:10.1097/00006842-199903000-00006 · Cited by 1,890 · cited 1× · see citing works
“First, we focused on male participants only since it is known that estradiol and progestins modify the endocrine stress reaction to psychosocial stress (Kirschbaum et al., 1999).”
Sniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis
Herman, J. P., Ostrander, M. M., Mueller, N. K., & Figueiredo, H. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.08.006 · Cited by 1,322 · see citing works
Do stress reactions cause abdominal obesity and comorbidities?
Björntorp, P. A. (2001) · Obesity Reviews · doi:10.1046/j.1467-789x.2001.00027.x · Cited by 1,141 · see citing works
Stressor specificity of central neuroendocrine responses: implications for stress-related disorders
Pacák, K., & Palkovits, M. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.4.0436 · Cited by 926 · see citing works
Dressendörfer, R. A., Kirschbaum, C., Rohde, W., Stahl, F., & Strasburger, C. J. (1992) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(92)90294-s · Cited by 882 · see citing works
Intranasal insulin improves memory in humans
Benedict, C., Hallschmid, M., Hatke, A., Schultes, B., Fehm, H. L., Born, J., & Kern, W. (2004) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2004.04.003 · Cited by 699 · see citing works
HPA axis activation by a socially evaluated cold-pressor test
Schwabe, L., Haddad, L., & Schächinger, H. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.03.001 · Cited by 698 · see citing works
Self-citationChrousos, G. P. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801278 · Cited by 637 · see citing works
The role of insulin receptor signaling in the brain
Plum, L., Schubert, M., & Brüning, J. C. (2005) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2005.01.008 · Cited by 604 · see citing works
Schommer, N. C., Hellhammer, D. H., & Kirschbaum, C. (2003) · Psychosomatic Medicine · doi:10.1097/01.psy.0000035721.12441.17 · Cited by 561 · see citing works
Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Schwartz, M. W., Sipols, A. J., Marks, J. L., Sanacora, G., White, J. D., Scheurink, A., Kahn, S. E., Baskin, D. G., Woods, S. C., & Figlewicz, D. P. (1992) · Endocrinology · doi:10.1210/endo.130.6.1597158 · Cited by 555 · see citing works
Neuroendocrine aspects of hypercortisolism in major depression
Parker, K. J., Schatzberg, A. F., & Lyons, D. M. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(02)00016-8 · Cited by 455 · see citing works
The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
Benoit, S. C., Air, E. L., Coolen, L. M., Strauss, R., Jackman, A., Clegg, D. J., Seeley, R. J., & Woods, S. C. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09048.2002 · Cited by 417 · see citing works
UNGER, J., Livingston, J. H., & Moss, A. (1991) · Progress in Neurobiology · doi:10.1016/0301-0082(91)90015-s · Cited by 403 · see citing works
Intranasal Insulin Reduces Body Fat in Men but not in Women
Hallschmid, M., Benedict, C., Schultes, B., Fehm, H.-L., Born, J., & Kern, W. (2004) · Diabetes · doi:10.2337/diabetes.53.11.3024 · Cited by 281 · see citing works
Insulin and Leptin as Adiposity Signals
Benoit, S. C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.267 · Cited by 266 · see citing works
Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis
Niswender, K. D., Baskin, D. G., & Schwartz, M. W. (2004) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2004.07.009 · Cited by 262 · see citing works
Obese men respond to cognitive but not to catabolic brain insulin signaling
Hallschmid, M., Benedict, C., Schultes, B., Born, J., & Kern, W. (2008) · International Journal of Obesity · doi:10.1038/sj.ijo.0803722 · Cited by 165 · see citing works
Effects of Fasting and Glucose Load on Free Cortisol Responses to Stress and Nicotine1
Kirschbaum, C., González‐Bono, E., Rohleder, N., Gessner, C., Pirke, K. M., Salvador, A., & Hellhammer, D. H. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.4.3882 · Cited by 141 · see citing works
PENHOAT, A., CHATELAIN, P. G., JAILLARD, C., & SAEZ, J. M. (1988) · Endocrinology · doi:10.1210/endo-122-6-2518 · Cited by 127 · see citing works
Effects of Fasting and Glucose Load on Free Cortisol Responses to Stress and Nicotine
Kirschbaum, C. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.4.1101 · Cited by 120 · see citing works
Fisher, S. J., Brüning, J. C., Lannon, S. M., & Kahn, C. R. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1447 · Cited by 111 · see citing works
SUPPRESSION OF COUNTERREGULATORY HORMONE RESPONSE TO HYPOGLYCEMIA BY INSULIN PER SE
DIAMOND, M. P., HALLARMAN, L., STARICK-ZYCH, K., JONES, T. W., CONNOLLY-HOWARD, M., TAMBORLANE, W. V., & SHERWIN, R. S. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-72-6-1388 · Cited by 107 · see citing works
Wirtz, P. H., von Känel, R., Mohiyeddini, C., Emini, L., Rüdisüli, K., Groessbauer, S., & Ehlert, U. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2586 · Cited by 95 · see citing works
Bell, M. E., Bhatnagar, S., Akana, S. F., Choi, S., & Dallman, M. F. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-17-06707.2000 · Cited by 87 · see citing works
Fries, E., Hellhammer, D. H., & Hellhammer, D. H. (2006) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2006.09.009 · Cited by 83 · see citing works
Fruehwald-Schultes, B., Kern, W., Bong, W., Wellhoener, P., Kerner, W., Born, J., Fehm, H. L., & Peters, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.5953 · Cited by 75 · cited 4× · see citing works
“In contrast to this attenuating effect of intranasally administered insulin on the basal HPA axis activity, other studies showed that high levels of systemic hyperinsulinemia during euglycemic glucose clamps could directly activate the HPA axis secretory activity in rats (Chan et al., 2005) and humans ( Fruehwald-Schu…”
InfluentialManipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology?
Fehm, H. L., Perras, B., Smolnik, R., Kern, W., & Jan Born, A. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00540-9 · Cited by 69 · see citing works
Evidence that the brain of the conscious dog is insulin sensitive.
Davis, S. N., Colburn, C., Dobbins, R., Nadeau, S., Neal, D., Williams, P., & Cherrington, A. D. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117703 · Cited by 68 · see citing works
Chan, O. T. M., Inouye, K., Akirav, E. M., Park, E., Riddell, M. C., Vranić, M., & Matthews, S. G. (2004) · Endocrinology · doi:10.1210/en.2004-0607 · Cited by 64 · see citing works
Kerr, D., Reza, M., Smith, N., & Leatherdale, B. A. (1991) · Diabetes · doi:10.2337/diab.40.8.1057 · Cited by 55 · see citing works
Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans
Fruehwald‐Schultes, B., Kern, W., Jan Born, A., Fehm, H., & Peters, A. (2001) · International Journal of Obesity · doi:10.1038/sj.ijo.0801695 · Cited by 50 · see citing works
B. Löwe, R.L. Spitzer, S. Zipfel & W. Herzog: PHQ-D. Gesundheitsfragebogen für Patienten
Berth, H. (2003) · Zeitschrift für Medizinische Psychologie · doi:10.3233/zmp-2003-12_2_08 · Cited by 39 · see citing works
Lingenfelser, T., Overkamp, D., Renn, W., Buettner, U. W., Kimmerle, K., Schmalfuss, A., & Jakober, B. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.3.8772600 · Cited by 37 · see citing works
Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM.
Davis, M. R., Mellman, M., & Shamoon, H. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.5.8496333 · Cited by 32 · see citing works
Flagged first, then by citations
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Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357 · see citing works
Intranasal Treatment of Central Nervous System Dysfunction in Humans
Chapman, C. D., Frey, W. H., Craft, S., Danielyan, L., Hallschmid, M., Schiöth, H. B., & Benedict, C. (2013) · Pharmaceutical Research · doi:10.1007/s11095-012-0915-1 · Cited by 310 · see citing works
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Heni, M., Kullmann, S., Preissl, H., Fritsche, A., & Häring, H.-U. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.173 · Cited by 245 · see citing works
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Scherer, T., Sakamoto, K., & Buettner, C. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00498-x · Cited by 205 · see citing works
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Lee, S.-H., Zabolotny, J. M., Huang, H., Lee, H., & Kim, Y.-B. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.011 · Cited by 176 · see citing works
Zhang, H., Hao, Y., Manor, B., Novak, P., Milberg, W., Zhang, J., Fang, J., & Novak, V. (2015) · Diabetes · doi:10.2337/db14-1000 · Cited by 176 · see citing works
Ott, V., Benedict, C., Schultes, B., Born, J., & Hallschmid, M. (2012) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01490.x · Cited by 139 · see citing works
Hallschmid, M. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12934 · Cited by 113 · see citing works
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Schmid, V., Kullmann, S., Gfrörer, W., Hund, V., Hallschmid, M., Lipp, H., Häring, H., Preissl, H., Fritsche, A., & Heni, M. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13279 · Cited by 110 · see citing works
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Feld, G. B., Wilhem, I., Benedict, C., Rüdel, B., Klameth, C., Born, J., & Hallschmid, M. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.312 · Cited by 36 · see citing works
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- Authors
- Bohringer, A., Schwabe, L., Richter, S., & Schachinger, H.
- Affiliations
- Universität Trier (DE)
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 33
- Issue
- 10
- Pages
- 1394-1400
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2166722689
- Cited by
- 89
- References
- 42
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 7 · 2012: 5
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Universität zu Lübeck
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- intranasal insulin, hypothalamic-pituitary-adrenal axis, psychosocial stress, Trier Social Stress Test, cortisol, stress reactivity, heart rate, blood pressure, blood glucose, plasma insulin, HPA axis hyperactivity
- MeSH terms
- Administration, Intranasal, Adult, Blood Glucose, Blood Pressure, Electrocardiography, Heart Rate, Hormones, Humans, Hydrocortisone, Hypoglycemic Agents, Hypothalamo-Hypophyseal System, Insulin, Male, Neuropsychological Tests, Pituitary-Adrenal System, Saliva, Social Environment, Stress, Psychological, Young Adult
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