Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans

Abstract

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.

Research design and 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.

FIG. 1.

Study procedures.

FIG. 2.

Plasma glucose and insulin levels during day 2 hypoglycemia in healthy individuals fasted overnight following either day 1 euglycemia (Eugly), day 1 euglycemia and alprazolam (Eugly+Alp), day 1 hypoglycemia (Hypo), or day 1 hypoglycemia and alprazolam (Hypo+Alp).

FIG. 3.

Day 2 glucagon and growth hormone responses (baseline and final 30 min of hypoglycemia) in healthy individuals fasted overnight following either day 1 euglycemia (Eugly), day 1 euglycemia and alprazolam (Eugly+Alp), day 1 hypoglycemia (Hypo), or day 1 hypoglycemia and alprazolam (Hypo+Alp). *Final 30-min levels are significantly reduced (P < 0.05) compared with those of day 1 euglycemia. †Final 30-min levels are significantly reduced (P < 0.05) compared with day 1 euglycemia and alprazolam, day 1 hypoglycemia, and day 1 euglycemia.

FIG. 4.

Day 2 epinephrine, norepinephrine, and pancreatic polypeptide (baseline and final 30 min of hypoglycemia) in healthy individuals fasted overnight following either day 1 euglycemia (eugly), day 1 euglycemia and alprazolam (eugly+alp), day 1 hypoglycemia (hypo), or day 1 hypoglycemia and alprazolam (hypo+alp). *Final 30-min levels are significantly reduced (P < 0.05) compared with those of day 1 euglycemia. ‡Basal and final 30-min norepinephrine values are significantly reduced (P < 0.05) compared with those of day 1 euglycemia.

FIG. 5.

MSNA and hypoglycemia symptoms at baseline (gray boxes) and during final 30 min (black boxes) of day 2 hypoglycemia in healthy individuals fasted overnight following either day 1 euglycemia (Eugly), day 1 euglycemia and alprazolam (Eugly+Alp), day 2 hypoglycemia (Hypo), or day 2 hypoglycemia and alprazolam (Hypo+Alp). *Final 30-min levels are significantly reduced (P < 0.05) compared with those of day 1 euglycemia. †Final 30-min responses are significantly reduced (P < 0.05) compared with those of day 1 euglycemia and alprazolam, day 1 hypoglycemia, and day 1 euglycemia. ‡Basal and final 30-min levels are significantly reduced (P < 0.05) compared with those of prior euglycemia.