High-fat Diet Aggravates Islet Beta-cell Toxicity in Mice Treated with Clozapine

Background: Clozapine, an atypical antipsychotic drug, induces derangements in glucose homeostasis in certain patients. This study investigated the mechanisms of clozapine-induced beta-cell toxicity.Methods: Fifty-two healthy C57BL/6 male mice were randomized into 4 groups to study the effects of clozapine (group C, D) and a high-fat diet (group B, D). Three mice from each group were randomly selected to determine the amount of food intake on days 8-10, and their pancreases were removed for histological examination on day 11. The remaining 10 mice in each group were sacrificed at the 8th week to measure pancreatic insulin content (PIC).Results: Mice given clozapine for 8 weeks demonstrated trends of lower PIC. Thehistological examination of the pancreases retrieved on day 11 already revealed apoptotic changes and suppression of cell proliferation. Although mice fed high-fat chow gained weight, mice given both clozapine and a highfat diet showed less weight gain and more severe histological deterioration, and had the lowest PIC levels of the 4 groups.Conclusion: Pancreatic beta-cell apoptosis, suppression of cell proliferation, and trends of reduction in pancreatic insulin content were observed in mice taking clozapine. The findings of clozapine induced beta-cell toxicity were further aggravated when mice were concomitantly fed a high-fat diet.