Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics.
OBJECTIVE
Both conventional and second-generation antipsychotics have been associated with an increased risk for impaired glucose tolerance and diabetes mellitus. Though this has been largely attributed to weight gain, there may also be a direct, receptor-mediated effect of antipsychotics on glucose tolerance. We tested the hypothesis that antagonism of the serotonin (5-HT)-2 receptor impairs insulin sensitivity.


METHODS
Ten healthy male volunteers were included in a double-blind, placebo-controlled crossover study of a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic-hyperinsulinemic clamp technique. Subjects were treated with the alpha-1 adrenergic antagonist phenoxybenzamine in both parts of the study to control for ketanserin's effects at the level of this receptor.


RESULTS
Compared with the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4 +/- 3.6 mg/kg/min; ketanserin: 7.7 +/- 2.1 mg/kg/min; p = .047).


CONCLUSIONS
The selective 5-HT2 antagonist ketanserin impaired insulin sensitivity. This effect was possibly mediated by suppression of 5-HT(2A) receptor mediated glucose uptake in skeletal muscle.
Gilles
Maria
M
Central Institute of Mental Health, Mannheim, Germany. gilles@as200.zi-mannheim.de
Wilke
Annette
A
Kopf
Daniel
D
Nonell
Annemarie
A
Lehnert
Hendrik
H
Deuschle
Michael
M
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D004311:Double-Blind Method; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051246:Glucose Transport Proteins, Facilitative / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010919:Placebos; D012307:Risk Factors; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
D014150:Antipsychotic Agents; D001786:Blood Glucose; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D010919:Placebos; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D007650:Ketanserin; D005947:Glucose