Topiramate (TPM) is a novel neurotherapeutic agent. Clinical studies reported that TPM treatment reduced body weight and decreased fasting blood glucose levels in obese patients with or without type 2 diabetes. It is unclear whether the blood glucose-normalizing phenomenon observed during TPM treatment is a primary effect or the consequence of reduced food intake and weight loss. In the present studies, we chronically treated female Zucker diabetic fatty (ZDF) rats (fed with a diabetogenic diet) and db/db mice with TPM (30-300 mg/kg/day) to examine the effect of TPM on hyperglycaemia and its relationship with food intake and body weight gain. Our data showed that TPM treatment markedly reduced blood glucose levels in both ZDF rats and db/db mice without a significant reduction in body weight gain. Pair-fed db/db mice treated with the vehicle alone did not exhibit a significant decrease in blood glucose levels compared with mice fed ad libitum. TPM treatment increased glucose-stimulated insulin release by 2-3-fold during an oral glucose tolerance test in both ZDF rats and db/db mice. We also observed a 1.4-fold increase of pancreatic insulin content and heightened insulin immunostaining in pancreatic beta cells in db/db mice treated with TPM. Our data suggest that the antidiabetic effect of TPM is independent of the changes in body weight gain and food intake. Improved glucose-induced insulin release may, in part, underlie the mechanisms by which TPM ameliorates the hyperglycaemia.