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

J Clin Endocrinol Metab. 2018 Jun 1;103(6):2244-2252. doi: 10.1210/jc.2017-02717.

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.

Trial registration: ClinicalTrials.gov NCT02056249.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Blood Glucose
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Epinephrine / blood
  • Female
  • Glucagon / blood
  • Human Growth Hormone / blood
  • Humans
  • Hydrocortisone / blood
  • Hypoglycemia / diagnostic imaging
  • Hypoglycemia / metabolism*
  • Male
  • Norepinephrine / metabolism*
  • Positron-Emission Tomography

Substances

  • Blood Glucose
  • Human Growth Hormone
  • Glucagon
  • Hydrocortisone
  • Norepinephrine
  • Epinephrine

Associated data

  • ClinicalTrials.gov/NCT02056249