Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men.
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.
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany martin.heni@med.uni-tuebingen.de.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Martin
M
Heni
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Robert
R
Wagner
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Stephanie
S
Kullmann
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Sofiya
S
Gancheva
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.|Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Michael
M
Roden
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Andreas
A
Peter
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Norbert
N
Stefan
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Hubert
H
Preissl
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.
Hans-Ulrich
HU
Häring
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Andreas
A
Fritsche
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D003903:Deuterium; D059907:Functional Neuroimaging; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D050177:Overweight / Q000378:metabolism*; D013851:Thinness / Q000378:metabolism*; D055815:Young Adult
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D003903:Deuterium; D005947:Glucose