Stephanie Kullmann1,2, Ralf Veit1,2, Andreas Peter1,2,3, Rolf Pohmann4, Klaus Scheffler4,5, Hans-Ulrich Häring1,2,3,6, Andreas Fritsche1,2,3, Hubert Preissl1,2,3,6,7,8, Martin Heni1,2,3. 1. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany. 2. German Center for Diabetes Research, Tübingen, Germany. 3. Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany. 4. High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Tübingen, Germany. 5. Department for Biomedical Magnetic Resonance, Eberhard Karls University Tübingen, Tübingen, Germany. 6. Interfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany. 7. Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany. 8. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Abstract
Context: Insulin action in the human brain influences eating behavior, cognition, and whole-body metabolism. Studies investigating brain insulin rely on intranasal application. Objective: To investigate effects of three doses of insulin and placebo as nasal sprays on the central and autonomous nervous system and analyze absorption of insulin into the bloodstream. Design, Participants, and Methods: Nine healthy men received placebo or 40 U, 80 U, and 160 U insulin spray in randomized order. Before and after spray, brain activity was assessed by functional magnetic resonance imaging, and heart rate variability (HRV) was assessed from electrocardiogram. Plasma insulin, C-peptide, and glucose were measured regularly. Setting: General community. Results: Nasal insulin administration dose-dependently modulated regional brain activity and the normalized high-frequency component of the HRV. Post hoc analyses revealed that only 160 U insulin showed a considerable difference from placebo. Dose-dependent spillover of nasal insulin into the bloodstream was detected. The brain response was not correlated with this temporary rise in circulating insulin. Conclusions: Nasal insulin dose-dependently modulated regional brain activity with the strongest effects after 160 U. However, this dose was accompanied by a transient increase in circulating insulin concentrations due to a spillover into circulation. Our current results may serve as a basis for future studies with nasal insulin to untangle brain insulin effects in health and disease.
RCT Entities:
Context:Insulin action in the human brain influences eating behavior, cognition, and whole-body metabolism. Studies investigating brain insulin rely on intranasal application. Objective: To investigate effects of three doses of insulin and placebo as nasal sprays on the central and autonomous nervous system and analyze absorption of insulin into the bloodstream. Design, Participants, and Methods: Nine healthy men received placebo or 40 U, 80 U, and 160 U insulin spray in randomized order. Before and after spray, brain activity was assessed by functional magnetic resonance imaging, and heart rate variability (HRV) was assessed from electrocardiogram. Plasma insulin, C-peptide, and glucose were measured regularly. Setting: General community. Results: Nasal insulin administration dose-dependently modulated regional brain activity and the normalized high-frequency component of the HRV. Post hoc analyses revealed that only 160 U insulin showed a considerable difference from placebo. Dose-dependent spillover of nasal insulin into the bloodstream was detected. The brain response was not correlated with this temporary rise in circulating insulin. Conclusions: Nasal insulin dose-dependently modulated regional brain activity with the strongest effects after 160 U. However, this dose was accompanied by a transient increase in circulating insulin concentrations due to a spillover into circulation. Our current results may serve as a basis for future studies with nasal insulin to untangle brain insulin effects in health and disease.
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