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Iatrogenic hypoglycemia is one of the most serious acute complications in intensively insulin-treated diabetic patients and it remains the limiting factor in maintaining proper glycemic control.In particular, both recurrent exposure to hypoglycemia and longstanding diabetes can impair mechanisms that would normally correct hypoglycemia.As hypoglycemia can be debilitating and in more severe cases, fatal, understanding the mechanisms by which the body senses falls in blood glucose levels and initiates "counterregulatory" responses is crucial for the development of preventive therapies.One brain region in particular, the ventromedial hypothalamus (VMH), plays a vital role in monitoring energy homeostasis and initiating glucose counterregulation.This region of the brain expresses several types of neurons that respond to changes in ambient glucose levels by altering their firing rate, but their exact roles in glucose sensing and the mechanisms by which this is achieved are not well understood.Studies from various laboratories have demonstrated the importance of metabolic substrates and transporters, neuropeptides and neurotransmitters in not only conveying the glucoprivic signal to the brain, but also in initiating an appropriate counterregulatory response to hypoglycemia in the periphery.Our current understanding is that decreases in glucose are sensed by glucose responsive neurons using molecular mechanisms similar to those found in pancreatic beta-cells, and this glucoprivic signal then alters the firing rate of neurons to regulate the release of specific neurotransmitters that instigate a suitable counterregulatory hormone response.However, local changes in fuel substrates, changes in metabolic enzyme activity and synaptic inputs from other regions within the brain all serve to regulate the firing of these special neurons.Under normal circumstances these mechanisms work exquisitely to maintain blood glucose concentrations at near euglycemic levels.However, prior antecedent exposure to hypoglycemia and longstanding, poorly controlled diabetes can lead to adaptations within the brain that ultimately impair mechanisms that would normally help correct hypoglycemia.In particular, we and others have shown that these two pathophysiological conditions alter the metabolism of glucose and other fuel substrates within the hypothalamus which, in turn, leads to augmented release of the inhibitory neurotransmitter, GABA, within the VMH and suppression of glucose counterregulatory responses to subsequent bouts of hypoglycemia.Clearly, the mechanisms that detect hypoglycemia, its regulation and the pathophysiology of the defective counterregulatory responses in recurrent hypoglycemia and diabetes are complex and more work needs to be done in the future to fully elucidate these mechanisms and develop appropriate therapies to prevent or treat hypoglycemia.