Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia

Abstract

Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to monitor extracellular concentrations of norepinephrine (NE) and GABA. During systemic hypoglycemia, induced by insulin (1.0 U/kg), NE concentrations increased in the VMH (P < 0.05) and PVH (P = 0.06) in a bimodal fashion during the first 10 min and 20-30 min after insulin administration. In the VMH, GABA concentrations increased (P < 0.05) in a similar manner as NE. Extracellular NE concentrations in the LHA were slightly lower (P = 0.13), and GABA levels remained at baseline. The increases in NE and GABA in the VMH were absent during euglycemic clamp; however, NE in the PVH still increased, reflecting a direct response to hyperinsulinemia. On the basis of these data, we propose that the activity of noradrenergic afferents to the medial hypothalamus is increased during hypoglycemia and influences the activity of local GABAergic systems to activate appropriate physiological compensatory mechanisms.

The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia

“…Streptozotocin-induced diabetic rats have high GABA levels, low noradrenaline and reduced sympathetic nerve activity within the VMH [14]. Infusion of glucose into rat substantia nigral neurones increases GABA concentrations, whilst both the perfusion of the glucoprivic agent 2-deoxyglucose and systemic hypoglycaemia significantly reduced GABA in some [15] but not all studies [16,17]. Perfusion of the neurones with K-ATP channel activators lowered GABA levels, and antagonists increased them, in a manner analogous to the insulin secretory responses to these agents by pancreatic beta cells, demonstrating the close relationship between GABA, intracellular ATP levels, the K-ATP channel complex and glucose sensing.…”

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

“…Finally, neural pathways stimulated by hypoglycemia induce feeding behavior [2]. Hormone responses and symptoms of hypoglycemia tend to be blunted in DM patients treated with insulin, and it is likely that deficient responses to hypoglycemia result from recurrent severe hypoglycemia sustained over many years of insulin replacement [1] CNS mechanisms of autonomic and endocrine responses to hypoglycemia have been studied in dogs and in rodents, and these studies indicate participation of structures in brainstem as well as hypothalamus [3][4][5][6][7][8][9][10][11][12]. Although these animal studies have proven useful in elucidating aspects of neural circuitry underlying counterregulatory hormone secretion, symptom thresholds, per se, cannot be directly assessed in an animal model.…”

Extracellular Glucose in Rat Ventromedial Hypothalamus During Acute and Recurrent Hypoglycemia

“…Detection of local glucoprivation in the brain may be critical to the generation of appropriate compensatory responses (2). The ventromedial hypothalamus (VMH) has received attention because neurons in this area are responsive to both systemic hypoglycemia (3) and to changes in local extracellular glucose concentrations (4 -6). Local glucoprivation by application of the glucose-analogue 2-deoxyglucose into this area replicated the increased neuroendocrine and sympathoadrenal output characteristic of systemic hypoglycemia (7).…”