Modulation of β-Adrenergic Receptors in the Ventromedial Hypothalamus Influences Counterregulatory Responses to Hypoglycemia

Abstract

OBJECTIVENorepinephrine 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 METHODSAwake 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.RESULTSDespite 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).CONCLUSIONSLocal 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.

Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas

“…Local induction of glucopenia in this region results in increased systemic levels of GCG and epinephrine (7), and delivery of glucose in the VMH during systemic glucopenia prevents the release of these hormones (6). Increasing adrenergic signaling in the VMH increases the GCG response to hypoglycemia, whereas blocking adrenergic signaling decreases the response (47). Furthermore, norepinephrine levels increase in the VMH during hypoglycemia (5), and norepinephrine can increase local production of IL-6 (27,32).…”

“…This relationship may be extrapolated to glucose-sensing regions of the brain. Szepietowski et al (47) showed that modulating adrenergic signaling in the glucosesensing ventromedial hypothalamus (VMH) modulates the GCG response to insulin-induced hypoglycemia in rats. Moreover, endogenous production of norepinephrine in this region increases during hypoglycemia (5).…”

“…Prior work indicates the importance of the CNS for a full counterregulatory (GCG, epinephrine) response to hypoglycemia (47). Knowing that plasma IL-6 levels rise during hypoglycemia (12), we sought to determine whether central IL-6 could modulate GCG secretion in response to this alternative stressor.…”

β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

“…Previous studies have shown that the activation of VMH neurons during hypoglycaemia is in part mediated by the local synaptic release of noradrenaline (norepinephrine) [11], an effect that appears to be specifically mediated via β 2 -adrenergic receptors (B2ARs), which act to modulate the magnitude of the adrenaline and to lesser extent the glucagon responses to insulin-induce hypoglycaemia [12]. The current study was undertaken to assess the whether the systemic delivery of the widely available long-acting specific B2AR agonist, formoterol, could promote glucose counter-regulation, thereby diminishing hypoglycaemia risk.…”

Need of Beta 3 Agonist in Today's World as Oral Hypoglycaemic and Antiobesity

“…In clinical scenario, fully fledged insulin therapy is often limited by the increased risk hypoglycemia which is severe in nature. [1] Thus, nowadays newer and safer regimens of oral hypoglycemic drugs are introduced out of which beta 3 adrenergic receptor agonists are showing a promising future in combating the menace of hyperglycemia or diabetes mellitus paired with obesity. These drugs showed significant selectivity for stimulating lipolysis at adipocytes and hence enhances oxygen utilisation and energy consumption.…”