Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis

Patients and animals with poorly controlled or uncontrolled diabetes present with diurnal hypersecretion of glucocorticoids and altered regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. Although some of these changes are reversed with insulin replacement therapy, neuroendocrine function is not always restored to normal, even with rigorous glycemic control. In addition, stress responsiveness is also impaired in diabetes and this has important implications in the way patients with diabetes cope with many stress challenges, including the metabolic challenge of insulin-induced hypoglycemia. HPA dysregulation in diabetes appears to involve complex interactions between impaired glucocorticoid negative feedback sensitivity and factors such as hypoinsulinemia, hyperglycemia and/or hypoleptinemia, that may increase central drive of the axis. This review examines some of the evidence indicating hyperactivation of the HPA axis in patients with diabetes. Using the streptozotocin-diabetic rat as a model of type-1 diabetes, we will focus on elucidating some of the mechanisms underlying HPA dysregulation in diabetes. Hyperactivation of the HPA axis in diabetes is associated with increased expression of hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal mineralocorticoid receptor (MR) mRNA. Although insulin replacement restores ACTH and corticosterone levels to normal, likely through glucocorticoid-mediated suppression of ACTH secretion, CRH and MR mRNA expression remain elevated. A better understanding of these mechanisms may be important in developing new treatment modalities for patients with diabetes mellitus.