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      Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans

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          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/m<sup>2</sup>) 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<sup>–6</sup>). 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.

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          Most cited references26

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          Glucose clamp technique: a method for quantifying insulin secretion and resistance.

          Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.
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            Diabetes, obesity, and the brain.

            Recent evidence suggests a key role for the brain in the control of both body fat content and glucose metabolism. Neuronal systems that regulate energy intake, energy expenditure, and endogenous glucose production sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes.
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              Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system.

              Excessive secretion of glucagon is a major contributor to the development of diabetic hyperglycemia. Secretion of glucagon is regulated by various nutrients, with glucose being a primary determinant of the rate of alpha cell glucagon secretion. The intra-islet action of insulin is essential to exert the effect of glucose on the alpha cells since, in the absence of insulin, glucose is not able to suppress glucagon release in vivo. However, the precise mechanism by which insulin suppresses glucagon secretion from alpha cells is unknown. In this study, we show that insulin induces activation of GABAA receptors in the alpha cells by receptor translocation via an Akt kinase-dependent pathway. This leads to membrane hyperpolarization in the alpha cells and, ultimately, suppression of glucagon secretion. We propose that defects in this pathway(s) contribute to diabetic hyperglycemia.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2020
                October 2020
                05 November 2019
                : 110
                : 11-12
                : 929-937
                Affiliations
                [_a] aDepartment of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital, Eberhard-Karls-University Tübingen, Tübingen, Germany
                [_b] bInstitute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany
                [_c] cGerman Center for Diabetes Research (DZD), Neuherberg, Germany
                [_d] dUniversity Pharmacy, University Hospital, Tübingen, Germany
                [_e] eHigh-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Tübingen, Germany
                [_f] fDepartment for Biomedical Magnetic Resonance, Eberhard-Karls-University Tübingen, Tübingen, Germany
                [_g] gInterfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard-Karls-University, Tübingen, Germany
                [_h] hInstitute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany
                [_i] iInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
                Author notes
                *Martin Heni, MD, Department of Internal Medicine IV, University Hospital Tübingen, Otfried-Müller-Strasse 10, DE–72076 Tübingen (Germany), martin.heni@med.uni-tuebingen.de
                Author information
                https://orcid.org/0000-0002-8462-3832
                Article
                504551 Neuroendocrinology 2020;110:929–937
                10.1159/000504551
                31689708
                be513bc4-98a5-46a3-a379-c5351d1561b4
                © 2019 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 26 July 2019
                : 04 November 2019
                Page count
                Figures: 3, Tables: 1, Pages: 9
                Categories
                Research Article

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Hypothalamus,Imaging,Insulin resistance,Pancreas,Insulin secretion

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