Acute Effects of Oral Dehydroepiandrosterone on Counterregulatory Responses During Repeated Hypoglycemia in Healthy Humans

Abstract

We tested the hypothesis that acute administration of oral dehydroepiandrosterone (DHEA) during episodes of repeated hypoglycemia can prevent the development of hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans. Twenty-seven individuals (16 men, 11 women) participated in two separate randomized, single-blind, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hypoglycemic clamps (2.9 mmol/L) with 800 mg of DHEA or placebo administered before each clamp. Day 2 consisted of a single 2-h hypoglycemic clamp (2.9 mmol/L) following either DHEA (1,600 mg) or placebo. A 3-tritiated glucose was used to determine glucose kinetics during hypoglycemia on day 2. Antecedent hypoglycemia with placebo resulted in significant reductions of epinephrine, norepinephrine, glucagon, growth hormone, cortisol, endogenous glucose production, and lipolytic and symptom responses. During hypoglycemia on day 2, DHEA prevented blunting of all neuroendocrine, autonomic nervous system (ANS), metabolic, and symptom counterregulatory responses following hypoglycemia on day 1. In summary, DHEA can acutely preserve a wide range of key neuroendocrine, ANS, and metabolic counterregulatory homeostatic responses during repeated hypoglycemia. We conclude that DHEA may have acute effects to protect against hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans.

Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

“…DHEA and its sulfated metabolite DHEA-sulfate have anti-GABA effects and may block GABA in the VMH and consequently have been shown to prevent the induction of HAAF by experimental hypoglycemia in nondiabetic humans. 56 In addition, selective serotonin reuptake inhibitors (SSRIs) amplify the central output of the ANS and have also been shown to mitigate a reduction in the counterregulatory response to hypoglycemia by antecedent hypoglycemia in nondiabetic humans 57 and in individuals with T1D. 58 To date, approaches targeting the interruption of HAAF by administration of adrenal steroids or SSRIs to reverse counterregulatory defects in patients with long-standing T1D and hypoglycemia unawareness have not been reported.…”

“…Another approach targeting the central mechanisms of HAAF involves administration of the adrenal steroid dehydroepiandrosterone (DHEA). DHEA and its sulfated metabolite DHEA‐sulfate have anti‐GABA effects and may block GABA in the VMH and consequently have been shown to prevent the induction of HAAF by experimental hypoglycemia in nondiabetic humans . In addition, selective serotonin reuptake inhibitors (SSRIs) amplify the central output of the ANS and have also been shown to mitigate a reduction in the counterregulatory response to hypoglycemia by antecedent hypoglycemia in nondiabetic humans and in individuals with T1D .…”

Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab

“…More recently, there has been significant interest in discovering how cytokine, purine, steroid, opiate, β 2 -adrenergic or serotonergic signalling may play roles in the development of IAH [22,[38][39][40][41][42]. These extracellular signals are able to modulate firing rates of glucose-sensing neurons.…”

“…This knowledge has been derived from laboratory-based research, which has enabled proof-of-concept clinical trials. For instance, the inhaled highly-selective β 2 -adrenoreceptor agonist formoterol fumerate was shown to amplify the CRR to hypoglycaemia in a small group of participants with type 1 diabetes [42], while oral dehydroepiandrostenedione (DHEA), which has both anti-corticosteroid and anti-GABA activity, blunted the suppressive effect of recurrent hypoglycaemia on subsequent hypoglycaemia CRR in individuals without diabetes [39]. It is interesting that many of these extracellular signals help coordinate the body's response to a wide variety of physiological stressors and play roles in both amplifying the acute response to a given stressor and initiating subsequent adaptive responses that are designed to protect cells during subsequent exposure to that stressor.…”

Potential Approaches to Prevent Hypoglycemia-Associated Autonomic Failure

“…Patients with rheumatoid arthritis were found to have lower levels of DHEAS, which was associated with reduced counter-regulatory hormonal responses during hypoglycemia 61 . Recently, another group studied the effect of DHEA administration on development of HAAF, suggesting that DHEA and DHEAS have anti-γ-aminobutyric (GABA), anticorticosteroid, stimulatory nitric oxide, and N-methyl-D-aspartate agonist effects, all of which could potentially improve counter-regulatory responses during recurrent hypoglycemia 62 . After antecedent hypoglycemia, subjects receiving placebo had a reduced counter-regulatory hormonal response, but those who received DHEA had a preserved counter-regulatory response.…”