In summary, our data suggest that in uncontrolled diabetes, increased HPA activity is caused by increased central drive at or above the level of the PVN. Insulin treatment only restores HPA activity at and below the pituitary level, presumably by GC-mediated suppression of ACTH secretion. We hypothesize that the defective HPA response to hypoglycaemia is at least in part due to a lack of a decrease in MR mRNA in response to hypoglycaemia, and diminished sensitivity of the pituitary and adrenal gland to stimulation. Interestingly, insulin treatment restores the HPA response, but not the defective epinephrine response. Therefore, defective epinephrine responses are not linked to defective HPA responses. Similarly, antecedent hypoglycaemia specifically impairs epinephrine responses, but not HPA responses to hypoglycaemia. These studies have revealed some of the mechanisms of impaired HPA function in diabetes and its impaired responsiveness to hypoglycaemia. Further investigations are essential for understanding poor counterregulation in insulin-treated diabetes and may lead to new strategies for preventing hypoglycaemia.