Influence of VMH fuel sensing on hypoglycemic responses

• The counter-regulatory hormone response to hypoglycemia is regulated by a multitude of inputs from CNS fuel sources, neurotransmitter systems, and neuropeptide systems providing information to the VMH regarding overall energy status.
• Prior exposure to hypoglycemia results in central adaptations that lead to the use of alternative fuels by glucose-sensing neurons.
• Similarly to recurrent hypoglycemia, adaptive changes in brain fuel metabolism in diabetes limit the capacity of glucose-sensing neurons to properly detect hypoglycemia.

Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose-sensing neurons in the ventromedial hypothalamus (VMH); these monitor energy status and regulate the release of neurotransmitters that instigate a suitable counter-regulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counter-regulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia, and the pathophysiology of defective counter-regulation in diabetes, are complex and need to be elucidated to permit the development of therapies that prevent or reduce the risk of hypoglycemia.