Cortisol Elevations Comparable to Those That Occur During Hypoglycemia Do Not Cause Hypoglycemia-Associated Autonomic Failure

Abstract

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemicstepped hypoglycemic clamps the day after saline or cortisol (1.3 ؎ 0.2 g ⅐ kg ؊1 ⅐ min (1). It is typically the result of the interplay of relative or absolute insulin excess and compromised physiological and behavioral defenses against developing hypoglycemia in type 1 diabetes (1,2) and advanced type 2 diabetes (1,3). The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural as well as adrenomedullary response and the resulting neurogenic [autonomic] symptom responses to a given level of subsequent hypoglycemia) and thus causes a vicious cycle of recurrent iatrogenic hypoglycemia (1-4). The clinical impact of HAAF, including the finding that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients is well documented (1,4). However, the mediator(s) and mechanisms(s) of HAAF are unknown (1,4).Davis and colleagues have suggested that the cortisol response to antecedent hypoglycemia mediates HAAF (5-7). They found that cortisol infusions, which raised mean plasma cortisol concentrations to ϳ32 g/dl, reduced autonomic neuroendocrine (among other) responses to hypoglycemia the following day in healthy subjects (5); effects on symptom responses were not reported (5). They also found that deficient cortisol secretion (in patients with primary adrenocortical failure) minimized the effects of antecedent hypoglycemia (6). These investigators presented evidence that intracerebroventricular cortisone (7) or cortisol (8), but not dexamethasone (8), reduced plasma epinephrine and norepinephrine responses to subsequent hypoglycemia. They also found that intravenous dehydroepiandrosterone, a putative glucocorticoid antagonist, blocked the effect of antecedent hypoglycemia to reduce these responses t...

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

“…We believe that the contrasting conclusions of earlier glucocorticoid infusion studies may be related to the dose of steroid administered. While supraphysiologic hypercortisolemia (as achieved by McGregor et al [17]) may play a role in modulating sympathoadrenal responses to hypoglycemia, more moderate cortisol elevations (as achieved by Raju et al [18] and by our hydrocortisone infusion study, with cortisol responses closer to those typically observed during hypoglycemia) do not appear to exert a similar effect.…”

“…Recent studies in human subjects have also challenged the cortisol hypothesis. In 2003, Raju et al (18) found that lowerdose cortisol infusions (1.0 -1.4 g ⅐ kg Ϫ1 ⅐ min Ϫ1 , or ϳ4 -6 mg/h) on day 1 had no effect upon day 2 sympathoadrenal responses to hypoglycemia. Our hydrocortisone infusion study results are consistent with those of Raju et al In our hands, low-dose day 1 hydrocortisone infusions (averaging 5 mg/h) had no effect upon day 2 sympathoadrenal responses to hypoglycemia.…”

“…In contrast, not all studies have supported this "cortisol hypothesis" for the generation of HAAF. Raju et al (18) found that lower-dose cortisol infusions, producing levels more comparable to those typically observed during hypoglycemia, had no impact upon subsequent sympathoadrenal responses to hypoglycemia. Similar results have been reported using rodent models, which also failed to detect an effect of antecedent glucocorticoid exposure upon subsequent adrenergic responses to hypoglycemia (19 -21).…”

Mechanisms of Hypoglycemia-Associated Autonomic Failure and Its Component Syndromes in Diabetes

“…However, the relevance of the phenomenon to the pathogenesis of HAAF has been questioned. Using an experimental design generally similar to that initially used by Davis et al (68) but with lower cortisol infusion doses, we found that cortisol elevations comparable to, indeed somewhat above, those that occur during hypoglycemia (ϳ26 g/dl) did not reduce the adrenomedullary or neurogenic symptom responses to hypoglycemia the following day in healthy individuals (71). Furthermore, an adrenocortical glucocorticoid response does not appear to be critical to the effect of antecedent hypoglycemia.…”

From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease

“…Another lab demonstrated cortisol-induced suppression of responses to hypoglycemia in human patients treated with high doses of adrenocorticotropic hormone to produce pharmacological cortisol levels (McGregor, Banarer, & Cryer, 2002). However, treatment with elevated levels of cortisol in the range normally measured during hypoglycemia did not reduce hypoglycemia-induced epinephrine secretion in a follow-up study (Raju, McGregor, & Cryer, 2003). Failure of glucocorticoid pretreatment to suppress responses to subsequent hypoglycemia has been reported in rodent studies.…”