Molecular regulation of the hypothalamo-pituitary-adrenal axis in streptozotocin-induced diabetes: Effects of insulin treatment

Increased hypothalamo-pituitary-adrenocortical (HPA) activity in diabetes i s likely important in the development of some pathologies associated with t he disorder. We hypothesized that central regulation of HPA activity differ s among normal, streptozotocin (STZ)-diabetic, and insulin-treated diabetic rats. Blood glucose, ACTH, and corticosterone were elevated, 8 d after ind ucing diabetes. Insulin treatment normalized these parameters. Plasma norep inephrine was similar in all groups, but epinephrine was lower in STZ-diabe tic and higher in insulin-treated rats vs. normals. Increased ACTH with dia betes corresponded with increased hypothalamic CRH mRNA, but no change in p ituitary POMC mRNA. With insulin-treatment, CRH mRNA remained elevated, and POMC mRNA was unaltered. Hippocampal MR mRNA expression was dramatically i ncreased with diabetes and, moreover, was not normalized by insulin. No dif ferences in GRm RNA were detected between normal and STZ-diabetic rats. How ever, insulin treatment increased GR mRNA levels in the paraventricular nuc leus and pituitary. We postulate that, in STZ-diabetes: 1) increased HPA ac tivity is caused by increased central drive at and/or above the level of th e paraventricular nucleus and is associated with decreased epinephrine; and 2) normalized pituitary-adrenal activity with insulin may be caused by the compensatory increase in GR mRNA allowing glucocorticoid-mediated suppress ion of ACTH secretion despite the residual increase in central HPA activity . Thus, insulin apparently restored HPA activity at and below the pituitary but, surprisingly, not above it.