Submitted on October 1, 2004
Accepted on March 1, 2005
HYPERGLYCEMIA DOES NOT INCREASE BASAL HYPOTHALAMO-PITUITARY-ADRENAL ACTIVITY IN DIABETES, BUT IT DOES IMPAIR THE HPA RESPONSE TO INSULIN-INDUCED HYPOGLYCEMIA
Owen Chan1, Karen E Inouye1, Eitan M Akirav1, Edward Park2, Michael C Riddell2, Stephen G Matthews3, and Mladen Vranic4*
1 Physiology, University of Toronto, Toronto, Ontario, Canada
2 Kinesiology and Health Science, York University, Toronto, Ontario, Canada
3 Physiology, University of Toronto, Toronto, Ontario, Canada; Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Medicine, University of Toronto, Toronto, Ontario, Canada
4 Physiology, University of Toronto, Toronto, Ontario, Canada; Medicine, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: mladen.vranic{at}utoronto.ca.
Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin-diabetic (65mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated and phloridzin-treated diabetic rats were either sacrificed after 8 days or subjected to a hypoglycemic (40mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and
inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ-diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia. In response to
hypoglycemia, rises in plasma ACTH and corticosterone were significantly lower in diabetic rats compared to controls. Insulin and phloridzin restored both ACTH and
corticosterone responses in diabetic animals. Hypothalamic CRH mRNA and pituitary pro-opiomelanocortin mRNA
expression increased following 2hrs of hypoglycemia in normal, insulin-treated and phloridzin-treated diabetic rats, but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal MR mRNA in control, insulin- and phloridzin-treated diabetic rats, but not uncontrolled diabetic rats, whereas glucocorticoid receptor mRNA was not altered by hypoglycemia. In conclusion, despite elevated basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that defects in the CRH response may be related to a defective MR response. It is intriguing that phloridzin did not restore basal HPA activity but it restored the HPA response to hypoglycemia, suggesting that defects in basal HPA function in diabetes are due to insulin deficiency, but impaired responsiveness to hypoglycemia appears to stem from chronic hyperglycemia.
