EVIDENCE THAT ELEVATED PLASMA-CORTICOSTERONE LEVELS ARE THE CAUSE OF REDUCED HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE GENE-EXPRESSION IN DIABETES

Uncontrolled diabetes mellitus causes both a sustained activation of t he hypothalamic-pituitary-adrenal (HPA) axis and reduced expression of corticotrophin-releasing hormone (CRH) mRNA in the hypothalamic parav entricular nucleus (PVN). To investigate the role of glucocorticoids i n the regulation of CRH mRNA expression in the PVN of diabetic rats, w e studied surgically adrenalectomized (ADX) and sham-operated male Spr ague-Dawley rats 4 days after i.v. injection of streptozotocin (STZ; 6 5 mg/kg i.v.) or vehicle. Among sham-operated animals, AM plasma corti costerone levels were significantly increased in diabetic as compared to nondiabetic animals (1.46+/-0.54 vs. 0.22+/-0.05 mu g/dl; P < 0.05) , and were positively correlated to both plasma ACTH levels (r = 0.74; P = 0.015) and adrenal gland weight (r = 0.70; P = 0.025). In contras t, CRH mRNA levels measured in the PVN by in situ hybridization were i nversely related to the plasma corticosterone level (r = -0.68; P = 0. 045). In a second experiment, both diabetic and nondiabetic ADX rats r eceived a continuous subcutaneous infusion of either corticosterone at one of two doses or its vehicle for 4 days. Among vehicle-treated ADX animals, STZ diabetes raised hypothalamic CRH mRNA levels, in contras t to the tendency for diabetes to lower CRH mRNA in intact rats in the first experiment. Corticosterone administration lowered CRH mRNA comp arably in both diabetic and nondiabetic ADX rats. In contrast, diabete s reduced arginine vasopressin (AVP) mRNA levels in the PVN of ADX rat s and blunted the inhibitory effect of glucocorticoids on AVP mRNA lev els in this setting. We conclude (1) glucocorticoids are necessary for the effect of diabetes to reduce hypothalamic CRH gene expression, si nce diabetes causes a paradoxical increase in CRH mRNA levels in adren alectomized animals; (2) glucocorticoid inhibition of hypothalamic CRH gene expression is intact in diabetic rats; and (3) the activation of the HPA axis by diabetes is associated with a proportionate decrease in PVN CRH gene expression. These findings support a model in which hy pothalamic factors additional to CRH activate the HPA axis in uncontro lled diabetes, and inhibit CRH gene expression indirectly by negative glucocorticoid feedback. (C) 1997 Elsevier Science B.V.