Chronic effects of clozapine administration on insulin resistance in rats: evidence for adverse metabolic effects

Chronic treatment with the atypical antipsychotics clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia and insulin resistance diabetes. The present study mainly aimed to investigate possible mechanisms underlying clozapine-induced hyperglycemia. Male Wistar albino rats were randomly divided into two groups (each consists of 12 rats). The first group received clozapine orally at a dose of 10mg/kg body weight daily for 6 weeks, while the other group received the drug vehicle only and served as the control group. At the end of the six weeks, hyperglycemia, hyperinsulinemia and insulin resistance, as indicated by Homeostatic model assessment of insulin resistance (HOMA-IR), were observed in the clozapine group as compared with the control group. This disturbance in glucose regulation was associated with non-significant changes in body weight, serum cortisol level, and hepatic glycogen content. The Clozapine group showed a significant increase in hepatic phosphorylase activity and in the gene expression level of hepatic glucose-6-phosphatse (G6Pase) enzymes compared to the control group. It can be concluded that clozapine-induced hyperglycemia and insulin resistance occur in a manner mostly independent of weight gain, and may be attributed to an increase in hepatic phosphorylase activity and increased expression level of G6Pase.