Kristina Melkersson1, Eva Jansson. 1. Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. Kristina.Melkersson@ki.se
Abstract
OBJECTIVES: Treatment with the atypical antipsychotic clozapine is frequently associated with metabolic side-effects such as weight gain, lipid abnormalities and diabetes mellitus. Since insulin is a hormone that is involved in both the regulation of body weight, as well as in lipid metabolism and glucose regulation, an effect of clozapine on insulin secretion and/or on insulin action - at least in part - might explain its capability to induce these side-effects. The aim of this study was therefore to examine the influence of clozapine on insulin release in vitro. METHODS: The effect of clozapine in three different concentrations, 10(-6), 10(-5) and 10(-4) M, was investigated on both basal (i.e. 3.3 mM glucose) and glucose-stimulated (i.e. 16.7 mM glucose) insulin release, using isolated rat islets of Langerhans. RESULTS: The presence of clozapine in the concentrations of 10(-6), 10(-5) and 10(4 )M significantly increased basal insulin release compared to the control after 4 h (but not after 1 h) of incubation. As regards the glucose-stimulated insulin release, the presence of clozapine in the concentrations of 10(-5) and 10(-4) M, but not in that of 10(-6) M, significantly inhibited the glucose-stimulated insulin release compared to the control after both 1 and 4 h of incubation. CONCLUSION: This study demonstrates that the atypical antipsychotic clozapine exerts dual effects on insulin release in vitro, through stimulating basal insulin release and inhibiting glucose-stimulated insulin release. Both these effects of clozapine on insulin release may contribute to its disadvantage inducing metabolic side-effects.
OBJECTIVES: Treatment with the atypical antipsychotic clozapine is frequently associated with metabolic side-effects such as weight gain, lipid abnormalities and diabetes mellitus. Since insulin is a hormone that is involved in both the regulation of body weight, as well as in lipid metabolism and glucose regulation, an effect of clozapine on insulin secretion and/or on insulin action - at least in part - might explain its capability to induce these side-effects. The aim of this study was therefore to examine the influence of clozapine on insulin release in vitro. METHODS: The effect of clozapine in three different concentrations, 10(-6), 10(-5) and 10(-4) M, was investigated on both basal (i.e. 3.3 mM glucose) and glucose-stimulated (i.e. 16.7 mM glucose) insulin release, using isolated rat islets of Langerhans. RESULTS: The presence of clozapine in the concentrations of 10(-6), 10(-5) and 10(4 )M significantly increased basal insulin release compared to the control after 4 h (but not after 1 h) of incubation. As regards the glucose-stimulated insulin release, the presence of clozapine in the concentrations of 10(-5) and 10(-4) M, but not in that of 10(-6) M, significantly inhibited the glucose-stimulated insulin release compared to the control after both 1 and 4 h of incubation. CONCLUSION: This study demonstrates that the atypical antipsychotic clozapine exerts dual effects on insulin release in vitro, through stimulating basal insulin release and inhibiting glucose-stimulated insulin release. Both these effects of clozapine on insulin release may contribute to its disadvantage inducing metabolic side-effects.