Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.