We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulininduced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulintreated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone. Diabetes
Increased hypothalamo-pituitary-adrenocortical (HPA) activity in diabetes is likely important in the development of some pathologies associated with the disorder. We hypothesized that central regulation of HPA activity differs among normal, streptozotocin (STZ)-diabetic, and insulin-treated diabetic rats. Blood glucose, ACTH, and corticosterone were elevated, 8 d after inducing diabetes. Insulin treatment normalized these parameters. Plasma norepinephrine was similar in all groups, but epinephrine was lower in STZ-diabetic and higher in insulin-treated rats vs. normals. Increased ACTH with diabetes corresponded with increased hypothalamic CRH mRNA, but no change in pituitary POMC mRNA. With insulin-treatment, CRH mRNA remained elevated, and POMC mRNA was unaltered. Hippocampal MR mRNA expression was dramatically increased with diabetes and, moreover, was not normalized by insulin. No differences in GR mRNA were detected between normal and STZ-diabetic rats. However, insulin treatment increased GR mRNA levels in the paraventricular nucleus and pituitary. We postulate that, in STZ-diabetes: 1) increased HPA activity is caused by increased central drive at and/or above the level of the 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 suppression 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.
Previous reports suggested that the rat placenta had a rather limited capacity for steroidogenesis, particularly with respect to progesterone production. We found that the basal zone in the rat placenta, which contains the steroidogenic giant cells, can be isolated by simple surgical separation, and using them for in vitro incubations, significant conversion of pregnenolone-7 alpha-3H to progesterone-1H could be demonstrated. The 5alpha-reduced metabolites of progesterone, as well as compounds of the delta4 pathway, including 17alpha-hydroxyprogesterone, androstenedione and testosterone were also isolated and characterized. When progesterone-7alpha-3H was added as precursor, most of it remained unmetabolized, but qualitatively identical products were isolated as were found when pregnenolong-7alpha-3H was used as precursor. Incubations of the whole placenta and of labyrinth tissue yielded relatively much lower progesterone-3H from pregnenolone-7alpha-3H. Our results have thus established that the rat placenta is a steroidogenic organ, just as in many other species. Past difficulties in isolating progesterone from in vitro studies may possibly be due to the intense activity of the enzyme 5alpha-reductase when the whole placenta was used.
Placental hypertrophy was induced in pregnant rats by daily treatment with estrone (0.5 microng) and progesterone (4 mg) from day 3 through 19 combined with ovariectomy on day 12 of pregnancy. The ratio of basal zone to whole placenta was 47% by weight in these enlarged placentae on day 20 of pregnancy but only 34% in normal placentae. In each case, the basal zone tissue was homogenized and the 10,000 x g supernatant fraction was used for in vitro incubation with [7alpha-3H]pregnenolone as the added substrate. The normal placental tissue synthesized more progesterone and testosterone but less androstenedione and 5alpha-pregnane-3,20-dione than the giant placentae. Utilization of the pregnenolone substrate by the giant placentae was subnormal. Addition of 200 IU of human chorionic gonadotropin (hCG) in vitro to normal basal zone placentae sharply increased the production of progesterone, 17alpha-hydroxyprogesterone, androstenedione and 5alpha-pregnane-3,20-dione. The giant placentage failed to respond to hCG. Thus, steroid-induced hypertrophied placentae in rats do not participate in a compensatory mechanism for steroid hormone production toward pregnancy maintenance.
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