Modulation of β-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia

Abstract

Objective: Norepinephrine is locally released into the ventromedial hypothalamus (VMH), a key brain glucose-sensing region in the response to hypoglycemia. As a result, this neurotransmitter may play a role in modulating counterregulatory responses. This study examines whether norepinephrine acts to promote glucose counterregulation via specific VMH β-adrenergic receptors (BAR).

Research design and methods: Awake male Sprague-Dawley rats received, via implanted guide cannulae, bilateral VMH microinjections of 1) artificial extracellular fluid, 2) B2AR agonist, or 3) B2AR antagonist. Subsequently, a hyperinsulinemic-hypoglycemic clamp study was performed. The same protocol was also used to assess the effect of VMH delivery of a selective B1AR or B3AR antagonist.

Results: Despite similar insulin and glucose concentrations during the clamp, activation of B2AR in the VMH significantly lowered by 32% (P < 0.01), whereas VMH B2AR blockade raised by 27% exogenous glucose requirements during hypoglycemia (P < 0.05) compared with the control study. These changes were associated with alternations in counterregulatory hormone release. Epinephrine responses throughout hypoglycemia were significantly increased by 50% when the B2AR agonist was delivered to the VMH (P < 0.01) and suppressed by 32% with the B2AR antagonist (P < 0.05). The glucagon response was also increased by B2AR activation by 63% (P < 0.01). Neither blockade of VMH B1AR nor B3AR suppressed counterregulatory responses to hypoglycemia. Indeed, the B1AR antagonist increased rather than decreased epinephrine release (P < 0.05).

Conclusions: Local catecholamine release into the VMH enhances counterregulatory responses to hypoglycemia via stimulation of B2AR. These observations suggest that B2AR agonists might have therapeutic benefit in diabetic patients with defective glucose counterregulation.

Figures

FIG. 1.

B2AR modulation in the VMH and its effect on GIR and counterregulatory hormones during the hypoglycemic clamp study. GIR (A) and hormonal responses for plasma epinephrine (B), glucagon (C), and norepinephrine (D) for rats receiving microinjection of the artificial extracellular fluid vehicle (control; n = 12), the B2AR antagonist ICI-118,551 (n = 12), or the B2AR agonist formoterol (n = 10) during the hyperinsulinemic-hypoglycemic glucose clamp. Results are presented as mean ± SEM. Post hoc linear contrasts to localized effects; *P < 0.05, **P < 0.01, and ***P < 0.001 vs. controls.

FIG. 2.

Effect of VMH B1AR or B3AR blockade on GIR and counterregulatory hormones during the hypoglycemic clamp study. GIR (A) as well as epinephrine (B), glucagon (C), and norepinephrine (D) responses for rats receiving microinjection of the artificial extracellular fluid vehicle (control; n = 12), the B1AR antagonist CGP 20712 (n = 7), and the B3AR antagonist SR59230A (n = 6) during the hyperinsulinemic-hypoglycemic glucose clamp. Results are presented as mean ± SEM. Post hoc linear contrasts to localized effects; *P < 0.05 vs. controls.