Repeated Activation of Noradrenergic Receptors in the Ventromedial Hypothalamus Suppresses the Response to Hypoglycemia

Activation of the adrenergic system in response to hypoglycemia is important for proper recovery from low glucose levels. However, it has been suggested that repeated adrenergic stimulation may also contribute to counterregulatory failure, but the underlying mechanisms are not known. The aim of this study was to establish whether repeated activation of noradrenergic receptors in the ventromedial hypothalamus (VMH) contributes to blunting of the counterregulatory response by enhancing local lactate production. The VMH of non-diabetic rats were infused with either artificial extracellular fluid, norepinephrine or salbutamol for 3hrs/d for three consecutive days before they underwent a hypoglycemic clamp with microdialysis to monitor changes in VMH lactate levels. Repeated exposure to norepinephrine or salbutamol suppressed both the glucagon and epinephrine responses to hypoglycemia compared to controls. Furthermore, antecedent norepinephrine and salbutamol treatments raised extracellular lactate levels in the VMH. To determine whether the elevated lactate levels were responsible for impairing the hormone response, we pharmacologically inhibited neuronal lactate transport in a subgroup of norepinephrine-treated rats during the clamp. Blocking neuronal lactate utilization improved the counterregulatory hormone responses in norepinephrine-treated animals, suggesting repeated activation of VMH β2-adrenergic receptors increases local lactate levels which in turn, suppresses the counterregulatory hormone response to hypoglycemia.