Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia

Abstract

. Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia. Am J Physiol Endocrinol Metab 282: E770-E777, 2002. First published December 11, 2001 10.1152/ajpendo.00447.2001.-We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of ␣-(1-24)-ACTH (100 g/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to ϳ45 g/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P ϭ 0.004, final plasma epinephrine levels of 489 Ϯ 64 vs. 816 Ϯ 113 pg/ml), sympathetic neural (P ϭ 0.0022, final plasma norepinephrine levels of 244 Ϯ 15 vs. 342 Ϯ 22 pg/ml), parasympathetic neural (P ϭ 0.0434, final plasma pancreatic polypeptide levels of 312 Ϯ 37 vs. 424 Ϯ 56 pg/ml), and neurogenic (autonomic) symptom (P ϭ 0.0097, final symptom score of 7.1 Ϯ 1.5 vs. 10.6 Ϯ 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus. epinephrine; norepinephrine; glucagon; diabetes; hypoglycemia-associated autonomic failure IATROGENIC HYPOGLYCEMIA is the limiting factor in the glycemic management of diabetes (4). It causes recurrent physical morbidity, and often psychosocial morbidity, in most patients with type 1 diabetes mellitus (T1DM) and in many with advanced type 2 diabetes mellitus (T2DM). It sometimes causes chronic disability and even premature death. Furthermore, because it precludes maintenance of true euglycemia over time, iatrogenic hypoglycemia limits full realization of the established microvascular benefits and the potential macrovascular benefits of aggressive glycemic therapy of diabetes (32, 33).Iatrogenic hypoglycemia is typically the result of the interplay of relative or absolute insulin excess and compromised glucose counterregulation in people with diabetes (5). With respect to compromised defenses against developing hypoglycemia, the concept of hypoglycemia-associated autonomic failure (HAAF) (4, 6, 7) posits that episodes of recent antecedent iatrogenic hypoglycemia cause 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 red...

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.…”

“…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. In a separate study, McGregor et al (17) showed that day 1 infusions of ␣-(1-24)-ACTH (producing high endogenous cortisol levels of 45 Ϯ 3 g/dl) also blunted day 2 catecholamine responses to hypoglycemia, lending additional support to antecedent hypercortisolemia as a possible mediator of HAAF.…”

“…In 1996, Davis et al (16) reported that human subjects receiving high-dose cortisol infusions exhibited blunted epinephrine responses to hypoglycemia on the following day. Subsequently, McGregor et al (17) infused ␣-(1-24)-ACTH (adrenocorticotrophic hormone), stimulating high endogenous cortisol levels; these authors also observed blunted day 2 catecholamine responses to hypoglycemia. In contrast, not all studies have supported this "cortisol hypothesis" for the generation of HAAF.…”

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

“…These results have not been fully replicated. 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).…”

Capture-related Hypoglycemia and Recovery in Free-ranging Black Rhinoceroses (Diceros bicornis bicornis)

“…Most individual rhinoceroses (22 of 28) had glucose values .65 mg/dl at S2 (range of 14-168 mg/dl). In other species, hypoglycemia is partially mediated by the autonomic neuroendocrine system (McGregor et al, 2002). For example, in Standardbred horses exercised on a treadmill, cortisol concentrations increased along with glucose within 5 min postexercise (Valberg et al, 1989).…”