The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men
Abstract
Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis.
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In the citing paper
“Previous findings from healthy men indicate that brain insulin most likely modulates both3.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“these studies were mainly performed in lean men3,4”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“brain insulin action increases whole-body insulin sensitivity”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“and stimulates glucose uptake into peripheral tissues3”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“Studies performed in healthy men found that insulin action in the brain suppresses endogenous glucose production3,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“The current study corroborates that insulin action in the human brain modulates peripheral insulin sensitivity3,4,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“Here, the effects on peripheral insulin sensitivity were comparable in timing and magnitude to previous findings obtained in lean men3,4.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“The current study corroborates that insulin action in the human brain modulates peripheral insulin sensitivity3,4,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“On the basis of our previous findings3,8, we assessed the insulin-induced response of hypothalamic cerebral blood flow (CBF) as a readout for hypothalamic insulin action.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“In line with experimental evidence from animals30, previous correlational findings from humans indicate a crucial role of insulin action in the hypothalamus for the modulation of whole-body glucose metabolism3,4.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“CBF was extracted from the hypothalamus as our region of interest, based on recent findings3,8.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In the citing paper
“the fMRI measurements indicated an involvement of the hypothalamus and striatum in these glucoregulatory effects of IN insulin, which, notably, were not found in obese individuals”
From Intranasal insulin (2021) · cites this paper as [80]
Citations
Cites
INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT*
Steele, R. D. (1959) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1959.tb44923.x · Cited by 1,680
Somatostatin and Its Receptor Family
Patel, Y. (1999) · Frontiers in Neuroendocrinology · doi:10.1006/frne.1999.0183 · Cited by 1,670
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
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719
Hypothalamic KATP channels control hepatic glucose production
Pocai, A., Lam, T. K. T., Gutierrez-Juarez, R., Obici, S., Schwartz, G. J., Bryan, J., Aguilar-Bryan, L., & Rossetti, L. (2005) · Nature · doi:10.1038/nature03439 · Cited by 645
Insulin Action in Brain Regulates Systemic Metabolism and Brain Function
Kleinridders, A., Ferris, H. A., Cai, W., & Kahn, C. R. (2014) · Diabetes · doi:10.2337/db14-0568 · Cited by 625
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572
Empirical optimization of ASL data analysis using an ASL data processing toolbox: ASLtbx
Wang, Z., Aguirre, G. K., Rao, H., Wang, J., Fernández‐Seara, M. A., Childress, A. R., & Detre, J. A. (2007) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2007.07.003 · Cited by 479
A brain-liver circuit regulates glucose homeostasis
Pocai, A., Obici, S., Schwartz, G. J., & Rossetti, L. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.11.001 · Cited by 392
Page, K. A., Chan, O., Arora, J., Belfort-DeAguiar, R., Dzuira, J., Roehmholdt, B., Cline, G. W., Naik, S., Sinha, R., Constable, R. T., et al. (2013) · JAMA · doi:10.1001/jama.2012.116975 · Cited by 379
Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart
Benedict, C., Hallschmid, M., Schmitz, K., Schultes, B., Ratter, F., Fehm, H. L., Born, J., & Kern, W. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301193 · Cited by 302
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 · cited 1×
“This phenomenon was first observed in overweight people, who appeared to be resistant to brain insulin action not only in terms of regional brain activity but also with regard to many functional consequences: whereas insulin in the brain influences food intake and body weight (1,3) in lean people, no such effects have…”
BackgroundCentral insulin action regulates peripheral glucose and fat metabolism in mice
Koch, L., Wunderlich, F. T., Seibler, J., Könner, A. C., Hampel, B., Irlenbusch, S., Brabant, G. E., Kahn, C. R., Schwenk, F., & Brüning, J. C. (2008) · Journal of Clinical Investigation · doi:10.1172/jci31073 · Cited by 278
Brain Insulin Controls Adipose Tissue Lipolysis and Lipogenesis
Scherer, T., O’Hare, J., Diggs‐Andrews, K. A., Schweiger, M., Cheng, B., Lindtner, C., Zieliński, E., Vempati, P., Su, K., Dighe, S. V., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.008 · Cited by 270
Impaired insulin action in the human brain: causes and metabolic consequences
Heni, M., Kullmann, S., Preissl, H., Fritsche, A., & Häring, H.-U. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.173 · Cited by 245
Self-citationTschritter, O., Preissl, H., Hennige, A. M., Stumvoll, M., Porubska, K., Frost, R., Marx, H., Klösel, B., Lutzenberger, W., Birbaumer, N., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604404103 · Cited by 223
Self-citationKinetics and specificity of insulin uptake from plasma into cerebrospinal fluid.
Schwartz, M. W., Sipols, A. J., Kahn, S. E., Lattemann, D. F., Taborsky, G. J., Bergman, R. N., Woods, S. C., & Porte, D. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.259.3.e378 · Cited by 191
Kullmann, S., Heni, M., Veit, R., Scheffler, K., Machann, J., Häring, H.-U., Fritsche, A., & Preissl, H. (2015) · Diabetes Care · doi:10.2337/dc14-2319 · Cited by 175
Self-citationHeni, M., Wagner, R., Kullmann, S., Veit, R., Mat Husin, H., Linder, K., Benkendorff, C., Peter, A., Stefan, N., Häring, H.-U., et al. (2014) · Diabetes · doi:10.2337/db14-0477 · Cited by 167
Self-citationObese 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
Dunn, J. P., Kessler, R. M., Feurer, I. D., Volkow, N. D., Patterson, B. W., Ansari, M. S., Li, R., Marks-Shulman, P., & Abumrad, N. N. (2012) · Diabetes Care · doi:10.2337/dc11-2250 · Cited by 148 · cited 1×
“The striatal dopamine receptor availability is associated with whole-body insulin sensitivity (41).”
BackgroundCentral Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition
Salameh, T. S., Bullock, K. M., Hujoel, I. A., Niehoff, M. L., Wolden‐Hanson, T., Kim, J., Morley, J. E., Farr, S. A., & Banks, W. A. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150307 · Cited by 136
Heni, M., Kullmann, S., Ketterer, C., Guthoff, M., Linder, K., Wagner, R. J., Stingl, K. T., Veit, R., Staiger, H., Häring, H., et al. (2012) · Diabetologia · doi:10.1007/s00125-012-2528-y · Cited by 113
Self-citationInsulin Activates Erk1/2 Signaling in the Dorsal Vagal Complex to Inhibit Glucose Production
Filippi, B., Yang, C. S., Tang, C., & Lam, T. K. T. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.09.005 · Cited by 112
Dash, S., Xiao, C., Morgantini, C., Koulajian, K., & Lewis, G. F. (2015) · Diabetes · doi:10.2337/db14-0685 · Cited by 108
Schilling, T. M., de Sá, D. S. F., Westerhausen, R., Strelzyk, F., Larra, M. F., Hallschmid, M., Savaskan, E., Oitzl, M. S., Busch, H., Naumann, E., et al. (2013) · Human Brain Mapping · doi:10.1002/hbm.22304 · Cited by 84
Insulin Action in the Human Brain: Evidence from Neuroimaging Studies
Kullmann, S., Heni, M., Fritsche, A., & Preissl, H. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12254 · Cited by 83
Self-citationEffects of Intranasal Insulin on Hepatic Fat Accumulation and Energy Metabolism in Humans
Gancheva, S., Koliaki, C., Bierwagen, A., Nowotny, P., Heni, M., Fritsche, A., Häring, H.-U., Szendroedi, J., & Roden, M. (2015) · Diabetes · doi:10.2337/db14-0892 · Cited by 81
Self-citationOral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion
Smeets, P. A. M., Vidarsdóttir, S., de Graaf, C., Stafleu, A., van Osch, M. J. P., Viergever, M. A., Pijl, H., & van der Grond, J. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00231.2007 · Cited by 80
Perrin, C., Knauf, C., & Burcelin, R. (2004) · Endocrinology · doi:10.1210/en.2004-0270 · Cited by 79
Heni, M., Kullmann, S., Ketterer, C., Guthoff, M., Bayer, M., Staiger, H., Machicao, F. E., Häring, H., Preissl, H. T., Veit, R., et al. (2013) · Human Brain Mapping · doi:10.1002/hbm.22223 · Cited by 77
Self-citationAge-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans
Wagner, R. J., Heni, M., Linder, K., Ketterer, C., Peter, A., Böhm, A., Hatziagelaki, E. E., Stefan, N., Staiger, H., Häring, H., et al. (2013) · Acta Diabetologica · doi:10.1007/s00592-013-0493-7 · Cited by 62
Self-citationRamnanan, C. J., Edgerton, D. S., & Cherrington, A. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.006 · Cited by 56
Cerebrocortical Beta Activity in Overweight Humans Responds to Insulin Detemir
Tschritter, O., Hennige, A. M., Preissl, H. T., Porubská, K., Schäfer, S., Lutzenberger, W., Machicao, F. E., Birbaumer, N., Fritsche, A., & Häring, H. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001196 · Cited by 52
Self-citationHeni, M., Kullmann, S., Ahlqvist, E., Wagner, R. J., Machicao, F. E., Staiger, H., Häring, H.-U., Almgren, P., Groop, L., Small, D. M., et al. (2016) · Diabetologia · doi:10.1007/s00125-016-4095-0 · Cited by 47
Self-citationGut-brain mechanisms controlling glucose homeostasis
Scarlett, J. M., & Schwartz, M. W. (2015) · F1000Prime Reports · doi:10.12703/p7-12 · Cited by 41
Insulin Half-Life in Normal and Diabetic Subjects.
Tomasi, T. B., Sledz, D., Wales, J. K., & Recant, L. (1967) · Experimental Biology and Medicine · doi:10.3181/00379727-126-43434 · Cited by 39
Nonsuppressed Glucagon After Glucose Challenge as a Potential Predictor for Glucose Tolerance
Wagner, R. J., Hakaste, L., Ahlqvist, E., Heni, M., Machann, J., Schick, F., OBBERGHEN, E. V., Stefan, N., Gallwitz, B., Tuomilehto, J., et al. (2016) · Diabetes · doi:10.2337/db16-0354 · Cited by 37
Self-citationOtt, V., Lehnert, H., Staub, J., Wönne, K., Jan Born, A., & Hallschmid, M. (2014) · Diabetes · doi:10.2337/db14-0931 · Cited by 36
Akt-Dependent and Isoform-Specific Regulation of Dopamine Transporter Cell Surface Expression
Speed, N. K., Matthies, H. J. G., Kennedy, J. P., Vaughan, R. A., Javitch, J. A., Russo, S. J., Lindsley, C. W., Niswender, K. D., & Galli, A. (2010) · ACS Chemical Neuroscience · doi:10.1021/cn100031t · Cited by 32
Coomans, C. P., Biermasz, N. R., Geerling, J. J., Guigas, B., Rensen, P. C. N., Havekes, L. M., & Romijn, J. A. (2011) · Diabetes · doi:10.2337/db10-1100 · Cited by 29
Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?
Dash, S., Xiao, C., Morgantini, C., Koulajian, K., & Lewis, G. F. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1371 · Cited by 18
Is Brain Insulin Action Relevant to the Control of Plasma Glucose in Humans?
Edgerton, D. S., & Cherrington, A. D. (2015) · Diabetes · doi:10.2337/db14-1666 · Cited by 18
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Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Central nervous pathways of insulin action in the control of metabolism and food intake
Kullmann, S., Kleinridders, A., Small, D. M., Fritsche, A., Häring, H.-U., Preissl, H., & Heni, M. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30113-3 · Cited by 233
Self-citationBrain insulin signalling in metabolic homeostasis and disease
Scherer, T., Sakamoto, K., & Buettner, C. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00498-x · Cited by 205
Daily, J. W., Kang, S., & Park, S. (2020) · BioFactors · doi:10.1002/biof.1703 · Cited by 147
Insulin action in the brain regulates both central and peripheral functions
Agrawal, R., Reno, C. M., Sharma, S., CHRISTENSEN, C. G., Huang, Y., & Fisher, S. J. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00642.2020 · Cited by 153
Metadata
- Authors
- Heni, M., Wagner, R., Kullmann, S., Gancheva, S., Roden, M., Peter, A., Stefan, N., Preissl, H., Häring, H.-U., & Fritsche, A.
- Affiliations
- German Center for Diabetes Research (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Helmholtz Munich (DE)
- Corresponding author
- Heni, Martin
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-02-07
- Volume
- 66
- Issue
- 7
- Pages
- 1797-1806
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2586809204
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 19 · 2017: 4
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Federal Ministry of Education and Research (01GI0925)
- Helmholtz-Gemeinschaft (Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases)
- European Foundation for the Study of Diabetes (Rising Star award supported by Novo Nordisk)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hypothalamus, striatum, endogenous glucose production, glucose uptake, hyperinsulinemia, intranasal insulin, brain insulin resistance, obesity, glucose metabolism, glucose homeostasis
- MeSH terms
- Adult, Blood Glucose, Brain, Deuterium, Gluconeogenesis, Glucose, Humans, Hypoglycemic Agents, Hypothalamus, Insulin, Magnetic Resonance Imaging, Male, Thinness, Glucose Clamp Technique, Case-Control Studies, Neostriatum, Overweight, Young Adult, Functional Neuroimaging
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