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      Noradrenergic Activity in the Human Brain: A Mechanism Supporting the Defense Against Hypoglycemia

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          Abstract

          Context

          Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated patients with diabetes, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine (NE) in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses.

          Objective

          To examine the potential role of brain noradrenergic (NA) activation in humans during hypoglycemia.

          Design

          A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with positron emission tomographic imaging.

          Participants

          Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp.

          Design

          Participants received intravenous injections of (S,S)-[ 11C] O-methylreboxetine ([ 11C]MRB), a highly selective NE transporter (NET) ligand, at baseline and during hypoglycemia.

          Results

          Hypoglycemia increased plasma epinephrine, glucagon, cortisol, and growth hormone and decreased [ 11C]MRB binding potential ( BP ND) by 24% ± 12% in the raphe nucleus ( P < 0.01). In contrast, changes in [ 11C]MRB BP ND in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P < 0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane.

          Conclusions

          Insulin-induced hypoglycemia initiated a complex brain NA response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity, and hunger, had increased NA activity, whereas the hypothalamus showed a NET-binding pattern that was associated with the individual’s CR response magnitude. These findings suggest that NA output most likely is important for modulating brain responses to hypoglycemia in humans.

          Abstract

          Hypoglycemia increases noradrenergic activity in the raphe nuclei, whereas changes in hypothalamic noradrenergic activity correlate with the counterregulatory response to hypoglycemia in humans.

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          Author and article information

          Journal
          J Clin Endocrinol Metab
          J. Clin. Endocrinol. Metab
          jcem
          The Journal of Clinical Endocrinology and Metabolism
          Endocrine Society (Washington, DC )
          0021-972X
          1945-7197
          June 2018
          23 March 2018
          23 March 2019
          : 103
          : 6
          : 2244-2252
          Affiliations
          [1 ]Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
          [2 ]PET Center, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut
          [3 ]Yale School of Public Health, Yale School of Medicine, New Haven, Connecticut
          [4 ]Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah
          [5 ]Department of Radiology, New York University Medical Center, New York, New York
          Author notes
          Correspondence and Reprint Requests:   Renata Belfort-DeAguiar, MD, PhD, 300 Cedar Street, TAC S135, New Haven, Connecticut 06520. E-mail: Renata.aguiar@ 123456yale.edu .
          Article
          PMC6456998 PMC6456998 6456998 jcem_201702717
          10.1210/jc.2017-02717
          6456998
          29590401
          9592048c-573b-44a8-b2f7-1f3117050423
          Copyright © 2018 Endocrine Society
          History
          : 14 December 2017
          : 20 March 2018
          Page count
          Pages: 9
          Funding
          Funded by: National Institute of Diabetes and Digestive and Kidney Diseases 10.13039/100000062
          Award ID: R01 DK20495
          Award ID: T32 DK 07058
          Award ID: P30 DK045735
          Funded by: National Center for Advancing Translational Science 10.13039/100006108
          Award ID: UL1 TR001863
          Categories
          Clinical Research Articles
          Diabetes, Pancreatic and Gastrointestinal Hormones
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