Topiramate ameliorates hyperglycaemia and improves glucose‐stimulated insulin release in ZDF rats and db/db mice

Abstract

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.

Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial

“…It has been observed that topiramate significantly enhanced glucosestimulated insulin release in DM2 rodent models, accompanied by an increased pancreatic insulin content. 21 In the meal test conducted here, we also observed that the reduced plasma glucose levels were associated with an enhanced insulin/glucose ratio, indicating a trend of increased postprandial insulin release. Even though the plasma free fatty acid (FFA) levels were also significantly lowered during the meal test, the insulin/FFA ratio did not show any clear difference between the groups, again suggesting that the peripheral insulin sensitivity was not different between two groups.…”

“…It has been reported in a pair-fed study that topiramate-treated db/db mice showed a statistically significant reduction in the blood glucose levels, whereas vehicle-treated db/db mice fed the same amount of food as that consumed by topiramatetreated mice, did not. 21 The mechanisms underlying the effect of topiramate on the HbA1c reduction as well as FPG levels in these patients are not clear yet. We did not observe a significant improvement in whole-body insulin sensitivity following topiramate treatment although this would have been expected considering the over-all effect on glucose control.…”

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

“…In addition, topiramate, a novel antiepileptic drug, with some similarities to ZNS, has been shown to attenuate OLZassociated weight gain (Liang et al, 2005;Wilkes et al, 2005a, b), decrease plasma glucose, and increase in vivo insulin sensitivity in adipocytes and skeletal muscle resulting from increases in adiponectin levels (Gustafson et al, 2003). Here, we have shown that subchronic ZNS treatment attenuates chronic OLZ-induced elevated blood glucose.…”

Short-term topiramate treatment does not improve insulin sensitivity or secretion in obese insulin-resistant women

“…A potential beneficial side effect is the dosedependent reduction in body weight, which was verified in healthy obese subjects (1,2,3,4). Moreover, animal studies show that topiramate has an insulin-sensitizing effect and improves obesity-associated b-cell dysfunction in rats, independently of any reduction in food intake and weight loss (5,6,7,8). In obese type 2 diabetes (T2DM) patients, long-term topiramate treatment led to a decrease in weight, HbA1c, and 2-h plasma glucose level in response to an oral glucose tolerance test (OGTT) (9,10,11).…”