Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124].
BACKGROUND
The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg-1) glucose tolerance test with minimal-model analysis.


METHODS
The study was designed as a double-blind, placebo-controlled, cross-over clinical trial. Diazepam (10 mg) and clonazepam (1 mg) were infused during 30 min to 15 male subjects with a mean age of 22 years (range: 20-29), after informed consent was given. Benzodiazepines were assayed by capillary gas chromatography with electron capture, insulin by radioimmunoassay and glucose by the enzymatic glucose oxidase method.


RESULTS
Both benzodiazepines induced significant psychotropic effects. The acute insulin responses (AIR) were significantly and negatively correlated with the clonazepam plasma concentrations (r = -0.609, P < 0.05, n = 14). However, the mean AIR was not significantly different between the benzodiazepine-treated subjects and the controls. In addition, the parameters of glucose assimilation were significantly decreased as compared with placebo in the subgroup of 7 subjects with plasma clonazepam concentrations higher than 6.0 ng ml-1 (median and lower limit of effective therapeutic concentrations): 1.37 +/- 0.3 versus 2.84 +/- 0.60 x 10(-2)min-1 (P = 0.028) for the coefficient of glucose tolerance (Kg), 2.18 +/- 0.29 versus 3.71 +/- 0.89 x 10(-4)microUml-1min-1 (P = 0.018) for insulin sensitivity (Si) and 1.80 +/- 0.39 versus 3.59 +/- 0.71 x 10(-2)min-1 (P = 0.028) for glucose effectiveness at basal insulin (Sg). These parameters were not significantly modified when diazepam was administered; plasma levels of this drug however, were below the effective therapeutic concentrations (300 ng ml-1) from min 15 after the end of the perfusion.


CONCLUSIONS
The present results suggest that a benzodiazepine, in particular clonazepam, may alter insulin secretion and insulin sensitivity after a single administration in healthy volunteers.
Chevassus
Hugues
H
Clinical Investigation Center, Saint-Eloi University Hospital, Section of Clinical Pharmacology, Montpellier, France.|Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France.
Mourand
Isabelle
I
Clinical Investigation Center, Saint-Eloi University Hospital, Section of Clinical Pharmacology, Montpellier, France.|Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France.
Molinier
Nathalie
N
Clinical Investigation Center, Saint-Eloi University Hospital, Section of Clinical Pharmacology, Montpellier, France.
Lacarelle
Bruno
B
Department of Pharmacokinetics, La Timone University Hospital, Marseille, France.
Brun
Jean-Frédéric
JF
Department of Clinical Physiology, Lapeyronie University Hospital, Montpellier, France.
Petit
Pierre
P
Clinical Investigation Center, Saint-Eloi University Hospital, Section of Clinical Pharmacology, Montpellier, France.|Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France.
D000328:Adult; D001569:Benzodiazepines / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects* / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005951:Glucose Tolerance Test / Q000379:methods; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male
D001786:Blood Glucose; D007328:Insulin; D001569:Benzodiazepines