Prevention of an increase in plasma cortisol during hypoglycemia preserves subsequent counterregulatory responses.

Abstract

The aim of this study was to determine whether preventing increases in plasma cortisol during antecedent hypoglycemia preserves autonomic nervous system counterregulatory responses during subsequent hypoglycemia. Experiments were carried out on 15 (8 male/7 female) healthy, overnightfasted subjects and 8 (4 male/4 female) age-and weightmatched patients with primary adrenocortical failure. 5 d before a study, patients had their usual glucocorticoid therapy replaced with a continuous subcutaneous infusion of cortisol programmed to produce normal daily circadian levels. Both groups underwent identical 2-d experiments. On day 1, insulin was infused at a rate of 1.5 mU/kg per min, and 2-h clamped hypoglycemia (53 Ϯ 2 mg/dl) was obtained during the morning and afternoon. The next morning, subjects underwent an additional 2-h hypoglycemic (53 Ϯ 2 mg/ dl) hyperinsulinemic clamp. In controls, day 2 steady state epinephrine, norepinephrine, pancreatic polypeptide, glucagon, growth hormone, and muscle sympathetic nerve activity were significantly blunted ( P Ͻ 0.01) compared with day 1 hypoglycemia. In marked contrast, when increases of plasma cortisol were prevented in the patient group, day 2 neuroendocrine, muscle sympathetic nerve activity, hypoglycemic symptoms, and metabolic counterregulatory responses were equivalent with day 1 results. We conclude that ( a ) prevention of increases of cortisol during antecedent hypoglycemia preserves many critical autonomic nervous system counterregulatory responses to subsequent hypoglycemia; ( b ) hypoglycemia-induced increases in plasma cortisol levels are a major mechanism responsible for causing subsequent hypoglycemic counterregulatory failure; and ( c ) our results suggest that other mechanisms, apart from cortisol, do not play a major role in causing hypoglycemia-associated autonomic failure. ( J. Clin. Invest. 1997. 100:429-438.)

Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation.

“…Chronic elevation of glucocorticoid levels decreases basal catecholamine levels and reduces stress-induced catecholamine release, metabolism, turnover, and synthesis in the PVH (42). Glucocorticoids, which are released by each glucoprivic bout (43), have been implicated in the pathophysiology of impaired glucoregulation in HAAF (44,45). Our results reveal C1 through C3 to be potential sites in which glucocorticoids could act to produce a loss of sensitivity to a subsequent glucoprivic challenge.…”

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

“…In 1996, Davis et al (16) reported that nondiabetic human subjects receiving two 2-h cortisol infusions (2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 or ϳ9 mg/h) exhibited blunted day 2 neuroendocrine responses to hypoglycemia. Lending further support to their cortisol hypothesis, these authors later reported that following day 1 hypoglycemia, patients with Addison's disease (who could not mount endogenous cortisol responses) had preserved day 2 counterregulatory responses to hypoglycemia (27). However, the latter study's findings were complicated by profoundly suppressed epinephrine responses (Ͻ200 pg/ml or Ͼ60% lower than the epinephrine responses from our control studies) in the Addison's patients, present even during the control studies; this may have limited the ability of antecedent hypoglycemia to exert an additional effect.…”

Diabetes Impairs Hypothalamo-Pituitary-Adrenal (HPA) Responses to Hypoglycemia, and Insulin Treatment Normalizes HPA but not Epinephrine Responses

“…Diabetes is characterized by high glucocorticoid concentrations and a lack of circadian periodicity in HPA activity, which may underlie unresponsiveness of the axis to stress (22,29 -34). Davis et al (35)(36)(37) suggested that partial impairment of the HPA counterregulatory response is due to recurrent exposure to high cortisol levels during hyperinsulinemic-euglycemic clamps. However, our work indicated that repeated exposure to elevated corticosterone in the absence of hyperinsulinemia does not diminish the HPA counterregulatory response (38).…”