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

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)-[C-11] 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 [C-11]MRB binding potential (BPND) by 24% 6 12% in the raphe nucleus (P < 0.01). In contrast, changes in [C-11]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.