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.

Figure 1

Diagram of study procedures.

Figure 2

Plasma glucose and plasma insulin concentrations during day 1 and day 2 studies.

Figure 3

Epinephrine, norepinephrine, pancreatic polypeptide, glucagon, growth hormone, and cortisol concentrations (change from baseline to final 30 min of morning hypoglycemic clamps) on days 1 and 2 in healthy individuals fasted overnight following either placebo or DHEA administration. *P < 0.04–0.0001 compared with day 2 placebo; †P < 0.04 compared with day 2 DHEA.

Figure 4

Glycerol and NEFA responses, rates of EGP, glucose disposal rate (GDR), and glucose infusion rate (GIR) (final 30 min of day 2 clamps) on days 1 and 2 in healthy individuals fasted overnight following either placebo or DHEA administration. *P < 0.04–0.009 compared with day 2 placebo.