Effect of combined treatment with clozapine and metformin on fasting blood glucose, insulin level, and expression of the glucose transporter-2 (GLUT2) in Sprague-Dawley rats

BACKGROUND Antipsychotic medications can cause an increase in blood glucose and the development of type II diabetes. Metformin may ameliorate these side effects. OBJECTIVE Assess whether or not metformin reduces the abnormalities in glucose metabolism that occur with use of the antipsychotic clozapine. METHODS Eighteen adult Sprague-Dawley (SD) rats were divided into three groups that were intragastrically administered saline, clozapine (20 mg/kg), or a combination of clozapine (20 mg/kg) and metformin (78 mg/kg) for 28 days. Fasting blood glucose was assessed at baseline and every seven days thereafter. The animals were euthanized on the 28(th) day at which time aortic blood was obtained to assess blood insulin and C-peptide by radioimmunoassay, and pancreatic tissue samples were collected and used to determine the expression of the glucose transporter-2 (GLUT2) by real-time polymerase chain reaction (RT-PCR) and Western Blot. RESULTS Fasting blood glucose in the clozapine group was significantly higher at the 14(th), 21(st), and 28(th) day compared to baseline, but rats receiving clozapine and metformin only had significantly elevated levels on the 14(th) day of treatment. However, repeated measures ANOVA found no statistically significant differences in blood glucose levels over time between the three groups (p=0.136). Multiple comparison tests found that the mean insulin level in the clozapine+metformin group was significantly lower than the levels in the clozapine and saline groups. There were statistically significant differences in the expression of GLUT2 mRNA (clozapine+metformin group < clozapine group < saline group) and in the expression of GLUT2 protein (clozapine+metformin group, clozapine group < saline group). CONCLUSION This study found a non-significant increase in fasting blood glucose in SD rats treated with clozapine that was partially counteracted by concurrent administration of metformin. Rats administered clozapine showed the expected decrease in the expression of GLUT2, but concurrent administration of metformin and clozapine for 28 days did not show the expected normalization of the expression levels of GLUT2.