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Antagonism of the Serotonin (5-HT)-2 Receptor and Insulin Sensitivity: Implications for Atypical Antipsychotics

From the Central Institute of Mental Health, Mannheim, Germany (M.G., A.W., D.K., A.N., M.D.); Department of Endocrinology and Metabolism, Otto-von-Guericke-University, Magdeburg, Germany (H.L.).

Address correspondence and reprint requests to Maria Gilles, MD, Central Institute of Mental Health, J5, 68159 Mannheim, Germany. E-mail: gilles{at}as200.zi-mannheim.de

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 -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).

Conclusion: 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.

Key Words: 5-HT₂ antagonism • impaired insulin sensitivity • euglycemic-hyperinsulinemic clamp technique

Abbreviations: 5-HT = 5-hydroxytryptamine (serotonin); BMI = body mass index; FPG = fasting plasma glucose; IS = insulin sensitivity; BP = blood pressure.

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