Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) and hypoglycemia-associated autonomic failure (HAAF)

Hypoglycemia is a profound threat to the brain since glucose is its preferred fuel. Thus, decreases in plasma glucose must be sensed and appropriate hormonal and neuroendocrine responses generated to restore glucose to safe levels (i.e. counterregulatory responses (CRR) to hypoglycemia). Recurrent hypoglycemia impairs these protective mechanisms, resulting in a potentially life-threatening condition known as hypoglycemia-associated autonomic failure (HAAF). During HAAF, the glycemic threshold is reset so that glucose levels must fall further before the CRR is initiated. The brain plays a critical role in sensing hypoglycemia and initiating the CRR. Additionally, many neurons may sense changes in plasma and extracellular glucose. However, the way in which central glucose sensing is integrated to lead to effective initiation of the CRR is unknown. Furthermore, the mechanisms by which this system becomes impaired during HAAF are also unknown. Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) are poised to serve an integrative function in glucose homeostasis. First, they sense glucose. Second, the VMN receives input from other glucose-sensing areas. Finally, the VMN projects to areas linked to the regulation of the sympathoadrenal system that mediates the CRR. This review discusses VMN glucosensing neurons relative to their capacity to play a role in the regulation of the CRR and the generation of HAAF. Glucosensing neurons in the hindbrain as well as peripheral glucosensors are also considered.