Journal Article

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

Hwang, Janice J, Elshafie, Ahmed, Chan, Owen, Sherwin, Robert S, Belfort-DeAguiar, Renata, Yeckel, Catherine W, Carson, Richard E, Gallezot, Jean-Dominique, Ding, Yu-Shin

2018

Overview

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

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Adrenergic agonists / Adult / Blood Glucose / Brain / Brain - diagnostic imaging / Brain - metabolism / Care and treatment / Cell membranes / Clinical s / Cortisol / Cytosol / Diabetes mellitus / Diabetes therapy / Diabetics / Diagnosis / Editor's Choice / Epinephrine / Epinephrine - blood / Female / Glucagon / Glucagon - blood / Glucocorticoids / Glucose / Glucose metabolism / Growth hormones / Health aspects / Hormones / Human Growth Hormone - blood / Humans / Hunger / Hydrocortisone - blood / Hypoglycemia / Hypoglycemia - diagnostic imaging / Hypoglycemia - metabolism / Hypothalamus / Insulin / Intravenous administration / Male / Medical examination / Motor activity / Neuroimaging / Norepinephrine / Norepinephrine - metabolism / Physiological aspects / Positron-Emission Tomography / Raphe nuclei / Somatotropin