Intensive insulin therapy to achieve euglycemia yields significant microvascular and macrovascular benefits for those with diabetes. Unfortunately, this approach also increases the frequency of hypoglycemic episodes. Prolonged and recurrent severe hypoglycemic, particularly in children, can cause permanent neuropsychological dysfunction, including learning disabilities. Normally, within minutes of a dangerous drop in glucose levels, glucagon and epinephrine act to raise plasma glucose concentrations. However, repeated episodes of hypoglycemia can weaken this counterregulatory system. Failure of central glucoreceptors to recognize hypoglycemia and activate glucagon and epinephrine release may be the most common cause of hypoglycemia-associated autonomic failure (HAAF). Currently little is known about the defects that cause this critical failure.

Our experiments seek a means to amplify neuronal responsiveness to hypoglycemia. Previous studies have shown that functional ATP-sensitive K+ channels are required for glucose responsiveness in ventromedial hypothalamus (VMH) neurons and for counterregulatory hormone release. Phosphoinositides, which can be produced by the enzyme PI3K, are well known to regulate KATP channel activity. Indeed, PI3K activation stimulates KATP channel opening in glucose-responsive hypothalamic neurons. Thus, our research seeks to determine how PI3K signaling in VMH neurons affects glucose counterregulation. Since in some tissues prolonged insulin exposure leads to impaired PI3K signaling, we hypothesize that this mechanism contributes to the dampened hypoglycemic response following recurrent hypoglycemia. Therefore we are examining how prior insulin exposure influences PI3K alteration of counterregulatory hormone release.