Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development

Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA) axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.