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

Abstract

Objective: Long-term treatment with topiramate reduces body weight and improves insulin sensitivity in obese humans. Our aim was to evaluate the effect of topiramate treatment for 4 weeks on insulin sensitivity and secretion, independent of weight loss. Design: Randomized, double-blind, crossover, placebo-controlled study. Methods: Thirteen obese (BMI 36.6G1.3 kg/m 2 (meanGS.E.M.)), insulin-resistant (homeostasis model of assessment-insulin resistance 2.0G0.2) women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 weeks, separated by a 4-week washout period. Insulin sensitivity and b-cell function were assessed using a two-step hyperinsulinemic euglycemic clamp with stable isotopes and a hyperglycemic clamp. Results: Hepatic and peripheral insulin sensitivities were not affected by topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 mU/m 2 per min) T: 17.5G0.8 vs P: 18.5G1.0 mmol/kg LBM per min, tZ1.016, PZ0.33; step 2 (insulin infusion rate 40 mU/m 2 per min) T: 27.9G3.2 vs P: 28.8G1.9 mmol/kg LBM per min, tZ0.418, PZ0.68)). Subjects lost a small amount of weight during the topiramate period (T: K1.0G0.2 vs P: K0.1G0.2 kg, tZ2842, PZ0.15). There were no changes in body fat mass, blood pressure, and fasting glucose. b-Cell function was not affected by topiramate as evidenced by an unaltered area under the curve of early (0-10 min; T: 1929.6G265.7 vs P: 2024.7G333.6 pmol/l, tZK0.357, PZ0.73) and late (80-120 min; T: 28 017.7G5029.9 vs P: 31 567.7G5376.2 pmol/l, tZK1.481, PZ0.16) phase insulin levels during hyperglycemia. The use of topiramate was associated with significant side effects such as paresthesia, nausea, dizziness, and concentration problems. Conclusions: Low-dose topiramate treatment for 4 weeks, relative to placebo, had no significant effect on insulin sensitivity in overweight/obese adult females without established diabetes.

Disruption of the hippocampal and hypothalamic blood–brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate

“…Significance was determined by a one-way analysis of variance followed by Newman-Keuls post-test between HF vs. LF, LF vs. LF TPM, and HF vs. HF TPM. *p < 0.05; # p < 0.001 studies [25,[46][47][48][49]. Topiramate treatment had no effect on non-fasted blood glucose in our model, however, that does not imply it did not affect insulin sensitivity.…”

A 5-Day High-Fat, High-Calorie Diet Impairs Insulin Sensitivity in Healthy, Young South Asian Men but Not in Caucasian Men

“…A 6-h 2-step hyperinsulinemic-euglycemic clamp was performed as described previously (27). In short, a primed constant infusion of glucose tracer ([6,6-2 H 2 ]-glucose; 0.22 mmol/kg/min) was used to determine rates of glucose appearance (R a ) and glucose disposal (R d ).…”

A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus

“…thiazolidinediones) promote weight gain [39][40][41]. Short-term topiramate treatment is associated with minimal weight loss and does not improve either insulin sensitivity or secretion [42]. However, longer term topiramate treatment promotes weight loss and increases insulin sensitivity [43].…”