In an attempt to define the hypothalamic-pituitary-adrenal (HPA) axis in non-insulin dependent diabetic rats (WBN/Kob), we measured plasma corticotropin releasing factor (CRF), as well as arginine vasopressin (AVP), ACTH, and corticosterone (B), CRF concentrations in the median eminence (ME), the remainder of the hypothalamus (rHY) and the neurointermediate lobe of the pituitary (NIL). We also measured Iodine-125-labeled ovine CRF ([125I]oCRF) binding in the brain and peripheral tissues. Body and thymus weight in WBN/Kob rats were significantly lower than in control Wistar rats, but adrenal weight was higher in WBN/Kob rats. Plasma ACTH levels were significantly higher in WBN/Kob rats than in the control rats. However, plasma CRF, AVP and B levels in WBN/Kob rats were not different from those in the control rats. The CRF concentration was significantly decreased in the ME of the diabetic rats, compared with control rats, but CRF concentrations in the rHY and NIL were unchanged in the two groups. A significant reduction in [125I]oCRF binding in the anterior pituitary was demonstrated in WBN/Kob rats, but no significant difference between the diabetic and control rats in CRF binding was observed in the frontal cortex, spleen or adrenal gland. These findings suggest that the HPA axis is chronically stimulated in the non-insulin dependent diabetic rats.