Poor glycemic control in diabetes, as well as prolonged stress, often cause sustained glucocorticoid secretion and hypothalamic-pituitary-adrenal (HPA) hyperactivity. However, the mechanism of HPA hyperactivation in diabetes is poorly understood. We investigated molecular factors underlying alteration of HPA mediators by comparing the effects of diabetes and restraint stress (45min/d): occasional (3 intermittent episodes) and repeated (20 consecutive episodes) restraint in non-diabetic and diabetic rats. Brains and pituitaries were collected on day 21 and mRNA expression was determined by in situ hybridization. As expected, diabetic groups were hyperglycemic (21.7+/-1.5mM). 21 days of diabetes increased pro-opiomelanocortin, basal corticosterone, hippocampal MR, and adrenal weight. Occasional stress did not change baseline parameters of HPA function in non-diabetic rats. In diabetic rats, occasional and repeated stress decreased pro-opiomelanocortin, basal corticosterone, and increased sensitivity of peak corticosterone response. Normalization of HPA parameters in diabetic stressed rats could guard against the high glucocorticoid levels associated with diabetes.