Renata Belfort-DeAguiar1, Jean-Dominique Gallezot2, Janice J Hwang1, Ahmed Elshafie1, Catherine W Yeckel3, Owen Chan4, Richard E Carson2, Yu-Shin Ding5, Robert S Sherwin1. 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.
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 (BPND) by 24% ± 12% in the raphe nucleus (P < 0.01). In contrast, changes in [11C]MRB BPND 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.
Context:Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treatedpatients 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 (BPND) by 24% ± 12% in the raphe nucleus (P < 0.01). In contrast, changes in [11C]MRB BPND 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 rathypothalamus 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.
Authors: Justine Y Hansen; Golia Shafiei; Jacob W Vogel; Kelly Smart; Carrie E Bearden; Martine Hoogman; Barbara Franke; Daan van Rooij; Jan Buitelaar; Carrie R McDonald; Sanjay M Sisodiya; Lianne Schmaal; Dick J Veltman; Odile A van den Heuvel; Dan J Stein; Theo G M van Erp; Christopher R K Ching; Ole A Andreassen; Tomas Hajek; Nils Opel; Gemma Modinos; André Aleman; Ysbrand van der Werf; Neda Jahanshad; Sophia I Thomopoulos; Paul M Thompson; Richard E Carson; Alain Dagher; Bratislav Misic Journal: Nat Commun Date: 2022-08-10 Impact factor: 17.694