Abstract
Mechanisms that underlie metabolic sensor acclimation to recurring insulin-induced hypoglycemia (RIIH) are unclear. Norepinephrine (NE) regulates ventromedial hypothalamic nucleus (VMN) gluco-stimulatory nitric oxide (NO) and gluco-inhibitory γ-aminobutryic acid (GABA) neuron signaling. Current research addressed the hypothesis that during RIIH, NE suppresses 5'-AMP-activated protein kinase (AMPK) reactivity in both populations and impedes counter-regulation. The brain is postulated to utilize non-glucose substrates, e.g. amino acids glutamine (Gln), glutamate (Glu), and aspartate (Asp), to produce energy during hypoglycemia. A correlated aim investigated whether NE controls pyruvate recycling pathway marker protein (glutaminase, GLT; malic enzyme, ME-1) expression in either metabolic-sensory cell population. Male rats were injected subcutaneously with vehicle or insulin on days 1-3, then pretreated on day 4 by intracerebroventricular delivery of the alpha1-adrenergic receptor (α1-AR) reverse-agonist prazocin (PRZ) or vehicle before final insulin therapy. PRZ prevented acute hypoglycemic augmentation of AMPK activation in each cell group. Antecedent hypoglycemic repression of sensor activity was reversed by PRZ in GABA neurons. During RIIH, nitrergic neurons exhibited α1-AR - dependent up-regulated GLT and α2-AR profiles, while GABA cells showed down-regulated α1-AR. LC-ESI-MS analysis documented a decline in VMN Glu, Gln, and Asp concentrations during acute hypoglycemia, and habituation of the former two profiles to RIIH. PRZ attenuated glucagon and corticosterone secretion during acute hypoglycemia, but reversed decrements in output of both hormones during RIIH. Results implicate adjustments in impact of α1-AR signaling in repressed VMN metabolic-sensory AMPK activation and counter-regulatory dysfunction during RIIH. Antecedent hypoglycemia may up-regulate NO neuron energy yield via α1-AR - mediated up-regulated pyruvate recycling.