Adrenal hypersensitivity precedes chronic hypercorticism in streptozotocin-induced diabetes mice.
Previous studies have demonstrated that type 1 diabetes is characterized by hypercorticism and lack of periodicity in adrenal hormone secretion. In the present study, we tested the hypothesis that hypercorticism is initiated by an enhanced release of ACTH leading subsequently to adrenocortical growth and increased output of adrenocortical hormones. To test this hypothesis, we used the streptozotocin (STZ)-induced diabetes mouse model and measured hypothalamic-pituitary-adrenal axis activity at different time points. The results showed that the expected rise in blood glucose levels induced by STZ treatment preceded the surge in corticosterone secretion, which took place 1 d after diabetes onset. Surprisingly, circulating ACTH levels were not increased and even below control levels until 1 d after diabetes onset and remained low until d 11 during hypercorticism. In response to ACTH (but not vasopressin), cultures of adrenal gland cells from 11-d diabetic mice secreted higher amounts of corticosterone than control cells. Real-time quantitative PCR revealed increased expression of melanocortin 2 and melanocortin 5 receptors in the adrenal glands at 2 and 11 d of STZ-induced diabetes. AVP mRNA expression in the paraventricular nucleus of the hypothalamus was increased, whereas hippocampal MR mRNA was decreased in 11-d diabetic animals. GR and CRH mRNAs remained unchanged in hippocampus and paraventricular nucleus of diabetic mice at all time points studied. These results suggest that sensitization of the adrenal glands to ACTH rather than an increase in circulating ACTH level is the primary event leading to hypercorticism in the STZ-induced diabetes mouse model.
Revsin
Yanina
Y
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, Leiden, The Netherlands. y.revsin@lacdr.leidenuniv.nl
van Wijk
Diane
D
Saravia
Flavia E
FE
Oitzl
Melly S
MS
De Nicola
Alejandro F
AF
de Kloet
E Ronald
ER
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000308:Adrenocortical Hyperfunction / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011863:Radioimmunoassay; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D018043:Receptors, Corticotropin / Q000235:genetics; D044101:Receptors, Melanocortin; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014667:Vasopressins / Q000235:genetics
D001786:Blood Glucose; D044103:Receptor, Melanocortin, Type 2; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D018161:Receptors, Mineralocorticoid; C086971:melanocortin 5 receptor; D014667:Vasopressins; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone