The Medial Amygdalar Nucleus: A Novel Glucose-Sensing Region That Modulates the Counterregulatory Response to Hypoglycemia

OBJECTIVE: To determine whether the medial amygdalar nucleus (MAN) represents a novel brain glucose-sensing region involved in the detection of hypoglycemia and generation of a counterregulatory hormone response. RESEARCH DESIGN AND METHODS: Fura-2 calcium imaging was used to assess glucose responsivity in neurons isolated from the MAN and single-cell real-time reverse transcription PCR used to examine gene expression within glucose-responsive neurons. In vivo studies with local MAN perfusion of the glucoprivic agent, 2-deoxyglucose (2-DG), under normal and hypoglycemic conditions and also after MAN lesioning with ibotenic acid, were used to examine the functional role of MAN glucose sensors. In addition, retrograde neuronal tracer studies were used to examine reciprocal pathways between the MAN and the ventromedial hypothalamus (VMH). RESULTS: The MAN contains a population of glucose-sensing neurons (13.5%), which express glucokinase, and the selective urocortin 3 (UCN3) receptor CRH-R2, but not UCN3 itself. Lesioning the MAN suppressed, whereas 2-DG infusion amplified, the counterregulatory response to hyperinsulinemic hypoglycemia in vivo. However, 2-DG infusion to the MAN or VMH under normoglycemic conditions had no systemic effect. The VMH is innervated by UCN3 neurons that arise mainly from the MAN, and ∼1/3 of MAN UCN3 neurons are active during mild hypoglycemia. CONCLUSIONS: The MAN represents a novel limbic glucose-sensing region that contains characteristic glucokinase-expressing glucose-sensing neurons that respond directly to manipulations of glucose availability both in vitro and in vivo. Moreover, UCN3 neurons may provide feedback inhibitory regulation of the counterregulatory response through actions within the VMH and the MAN.