title: Insulin alone increases hypothalamo-pituitary-adrenal activity, and diabetes lowers peak stress responses.
abstract: Diabetes is associated with increased basal hypothalamo-pituitary-adrenal (HPA) activity and impaired stress responsiveness. Previously, we demonstrated that the HPA response to hypoglycemia is significantly impaired in diabetic rats. In this study our goals were to 1) differentiate between the effects of hyperinsulinemia and those of hypoglycemia per se, and 2) establish whether diabetes lowers peak stress responses. Normal and streptozotocin-diabetic rats were subjected to hyperinsulinemic-euglycemic glucose clamps to evaluate central and peripheral responses. These were compared with peak ACTH and corticosterone responses to restraint and hypoglycemia. Hyperinsulinemia increased CRH and vasopressin mRNA, and plasma ACTH and corticosterone in normal and diabetic rats. In normal animals, insulin-induced activation of ACTH and corticosterone was lower than the responses during either restraint or hypoglycemia. In contrast, ACTH and corticosterone activation in diabetic rats was similar with all three stressors. Pituitary-adrenal axis activation in diabetic animals was also much lower compared with that in normal controls. The response to hyperinsulinemia (euglycemia) was associated with increases in glucocorticoid receptor mRNA in the anterior pituitary and paraventricular nucleus. Hippocampal mineralocorticoid receptor mRNA expression was increased in normal, but not in diabetic, animals. We speculate that the ability to appropriately match the HPA response to the potency of a stressor is related to the ability to alter hippocampal mineralocorticoid receptor expression. In diabetes, this ability is impaired; hence, maximal HPA activation is greatly diminished. This is a novel observation that may have important implications in the treatment of impaired counterregulatory mechanisms in human diabetes.
authors.affiliation: Department of Physiology, University of Toronto, Medical Sciences Building, Room 3240, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.forename: Karen
authors.initials: K
authors.lastname: Inouye
authors.forename: Eitan
authors.initials: E
authors.lastname: Akirav
authors.forename: Edward
authors.initials: E
authors.lastname: Park
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
authors.forename: Mladen
authors.initials: M
authors.lastname: Vranic
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001835:Body Weight; D002395:Catecholamines / Q000378:metabolism; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003720:Densitometry; D003921:Diabetes Mellitus, Experimental; D006624:Hippocampus / Q000378:metabolism; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism / Q000502:physiology*; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological; D013997:Time Factors; D014667:Vasopressins / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D002395:Catecholamines; D006728:Hormones; D007328:Insulin; D012333:RNA, Messenger; D014667:Vasopressins; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone