Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans.
OBJECTIVE
To date, there are no data investigating the effects of GABA(A) activation on counterregulatory responses during repeated hypoglycemia in humans. The aim of this study was to determine the effects of prior GABA(A) activation using the benzodiazepine alprazolam on the neuroendocrine and autonomic nervous system (ANS) and metabolic counterregulatory responses during next-day hypoglycemia in healthy humans.


METHODS
Twenty-eight healthy individuals (14 male and 14 female, age 27 +/- 6 years, BMI 24 +/- 3 kg/m(2), and A1C 5.2 +/- 0.1%) participated in four randomized, double-blind, 2-day studies. Day 1 consisted of either morning and afternoon 2-h hyperinsulinemic euglycemia or 2-h hyperinsulinemic hypoglycemia (2.9 mmol/l) with either 1 mg alprazolam or placebo administered 30 min before the start of each clamp. Day 2 consisted of a single-step hyperinsulinemic-hypoglycemic clamp of 2.9 mmol/l.


RESULTS
Despite similar hypoglycemia (2.9 +/- 1 mmol/l) and insulinemia (672 +/- 108 pmol/l) during day 2 studies, GABA(A) activation with alprazolam during day 1 euglycemia resulted in significant blunting (P < 0.05) of ANS (epinephrine, norepinephrine, muscle sympathetic nerve activity, and pancreatic polypeptide), neuroendocrine (glucagon and growth hormone), and metabolic (glucose kinetics, lipolysis, and glycogenolysis) counterregulatory responses. GABA(A) activation with alprazolam during prior hypoglycemia caused further significant (P < 0.05) decrements in subsequent glucagon, growth hormone, pancreatic polypeptide, and muscle sympathetic nerve activity counterregulatory responses.


CONCLUSIONS
Alprazolam activation of GABA(A) pathways during day 1 hypoglycemia can play an important role in regulating a spectrum of key physiologic responses during subsequent (day 2) hypoglycemia in healthy man.
Hedrington
Maka S
MS
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Farmerie
Stephnie
S
Ertl
Andrew C
AC
Wang
Zhihui
Z
Tate
Donna B
DB
Davis
Stephen N
SN
D000328:Adult; D000525:Alprazolam / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology; D005934:Glucagon / Q000097:blood; D006706:Homeostasis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D055815:Young Adult
D001786:Blood Glucose; D018757:GABA Modulators; D007328:Insulin; D011963:Receptors, GABA-A; D005934:Glucagon; D000525:Alprazolam