title: Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men.
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.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany robert.wagner@med.uni-tuebingen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Wagner
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Institute of Medical Psychology and Behavioral Neurobiology/fMEG Center, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kullmann
authors.affiliation: German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Institute of Medical Psychology and Behavioral Neurobiology/fMEG Center, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Veit
authors.affiliation: Institute of Medical Psychology and Behavioral Neurobiology/fMEG Center, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Haliza
authors.initials: H
authors.lastname: Mat Husin
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Linder
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Benkendorff
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Institute of Medical Psychology and Behavioral Neurobiology/fMEG Center, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Preissl
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D059907:Functional Neuroimaging; D015309:Glucose Clamp Technique; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007031:Hypothalamus / Q000098:blood supply / Q000187:drug effects*; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D008279:Magnetic Resonance Imaging; D008297:Male; D009765:Obesity; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin