Martin Heni1,2,3, Robert Wagner4,5,6, Caroline Willmann4,5,6, Benjamin Assad Jaghutriz4,5,6, Andreas Vosseler4,5,6, Christian Kübler4,5,6, Verena Hund7, Klaus Scheffler8,9, Andreas Peter4,5,6, Hans-Ulrich Häring4,5,6, Hubert Preissl4,5,6,10,11,12, Stephanie Kullmann5,6, Andreas Fritsche4,5,6. 1. Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital, Eberhard-Karls-University Tübingen, Tübingen, Germany, martin.heni@med.uni-tuebingen.de. 2. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany, martin.heni@med.uni-tuebingen.de. 3. German Center for Diabetes Research (DZD), Neuherberg, Germany, martin.heni@med.uni-tuebingen.de. 4. Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital, Eberhard-Karls-University Tübingen, Tübingen, Germany. 5. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany. 6. German Center for Diabetes Research (DZD), Neuherberg, Germany. 7. University Pharmacy, University Hospital, Tübingen, Germany. 8. High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Tübingen, Germany. 9. Department for Biomedical Magnetic Resonance, Eberhard-Karls-University Tübingen, Tübingen, Germany. 10. Interfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard-Karls-University, Tübingen, Germany. 11. Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany. 12. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Abstract
BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS:Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS:Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, β = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, β = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.
RCT Entities:
BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS:Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, β = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, β = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.
Authors: Stephanie Kullmann; Julia Hummel; Robert Wagner; Corinna Dannecker; Andreas Vosseler; Louise Fritsche; Ralf Veit; Konstantinos Kantartzis; Jürgen Machann; Andreas L Birkenfeld; Norbert Stefan; Hans-Ulrich Häring; Andreas Peter; Hubert Preissl; Andreas Fritsche; Martin Heni Journal: Diabetes Care Date: 2022-02-01 Impact factor: 19.112
Authors: Robert Wagner; Sabine S Eckstein; Hajime Yamazaki; Felicia Gerst; Jürgen Machann; Benjamin Assad Jaghutriz; Annette Schürmann; Michele Solimena; Stephan Singer; Alfred Königsrainer; Andreas L Birkenfeld; Hans-Ulrich Häring; Andreas Fritsche; Susanne Ullrich; Martin Heni Journal: Nat Rev Endocrinol Date: 2021-10-20 Impact factor: 43.330
Authors: Katsiaryna Prystupa; Rebecka Renklint; Youssef Chninou; Julia Otten; Louise Fritsche; Sebastian Hoerber; Andreas Peter; Andreas L Birkenfeld; Andreas Fritsche; Martin Heni; Robert Wagner Journal: BMJ Open Diabetes Res Care Date: 2022-09
Authors: Sonja C Schriever; Dhiraj G Kabra; Katrin Pfuhlmann; Peter Baumann; Emily V Baumgart; Joachim Nagler; Fabian Seebacher; Luke Harrison; Martin Irmler; Stephanie Kullmann; Felipe Corrêa-da-Silva; Florian Giesert; Ruchi Jain; Hannah Schug; Julien Castel; Sarah Martinez; Moya Wu; Hans-Ulrich Häring; Martin Hrabe de Angelis; Johannes Beckers; Timo D Müller; Kerstin Stemmer; Wolfgang Wurst; Jan Rozman; Ruben Nogueiras; Meri De Angelis; Jeffery D Molkentin; Natalie Krahmer; Chun-Xia Yi; Mathias V Schmidt; Serge Luquet; Martin Heni; Matthias H Tschöp; Paul T Pfluger Journal: J Clin Invest Date: 2020-11-02 Impact factor: 14.808