The effect of short term Topiramate treatment on insulin secretion, glucose- and lipid metabolism in obese women

Both obesity and type 2 diabetes mellitus are serious and growing global
problems. Over 80% of type 2 diabetic patients are overweight or obese. Both
obesity and type 2 diabetes mellitus are characterized by insulin resistance of
the liver, skeletal muscle and adipose tissue. Therefore, it is likely that
insulin resistance is the major underlying pathogenetic defect in obese type 2
diabetic patients. The most common treatment for obesity is life-style changes,
such as changing diets and/or increasing physical activity. However, this is
often insufficient to obtain the desired amount of weight loss. Lately, the
development of antiobesity agents has progressed rapidly. One of the medicines
tested is Topiramate.
Topiramate is a registered broad-spectrum neuro-therapeutic agent. Patients
show a striking dose dependent weight reduction after long-term treatment with
Topiramate (up to 6.3% weight loss). Furthermore, Topiramate treatment
increases the odds ratio of having normal glucose tolerance compared to placebo
after 60 weeks of treatment. However, patients treated with long-term high-dose
Topiramate show significant side effects. The exact mechanism behind the
drug-induced weight loss is not yet known, animal studies show a decrease in
food intake and an increase in total energy expenditure after long-term
Topiramate treatment.
Animal studies show that short-term Topiramate treatment has an
insulin-sensitizing effect in female obese rats independently of the decrease
in food intake or weight loss. Zucker diabetic fatty rats, who were fed
Topiramate 100 mg/kg for 7-9 days, showed an increase in whole body glucose
disposal of 35%, as well as a 40% increase in the ability of insulin to
suppress endogenous glucose production without losing weight.
Other animal studies in rodents show that beside an insulin sensitizing effect,
Topiramate also exert direct action on insulin secreting cells, in particular
it improves the obesity associated ß-cell dysfunction. Topiramate treatment
counteracts hyperglycemia and increases insulin levels upon glucose tolerance
tests in obese rodents.
This study is meant to elucidate the effect of short-term low-dose Topiramate
treatment on insulin sensitivity, lipid metabolism and insulin secretion,
independently of weight loss, in obese women. If this study demonstrates an
improvement of insulin sensitivity in liver, skeletal muscle and adipose tissue
and improvement glucose stimulated insulin secretion of the ß-cell, it may be
worthwhile to further study the mechanism of action of Topiramate and develop
Topiramate analogues, for the treatment of obesity, the metabolic syndrome and
type 2 DM. Since these conditions are emerging into worldwide epidemics, it is
of the utmost importance to find improve and extend the treatment options for
these conditions.

•To determine the effect of short-term Topiramate treatment on glucose
metabolism including endogenous glucose production, whole body glucose disposal
and glucose oxidation in obese women.
•To determine the effect of short-term Topiramate on lipid metabolism including
whole body lipolysis, lipid oxidation and blood cholesterol levels in obese
women.
•To determine the effect of short-term Topiramate on ß-cell sensitivity to
glucose, divided in the early and late response of insulin secretion.

Double blind randomized cross-over placebo controlled intervention study.

4 weeks Topiramate (first week 25 mg od (evening); second week 25 mg bid; third
and fourth week 25 mg od (morning) + 50 mg od (evening)) and 4 weeks Placebo.

Subjects will be admitted at the research center for two whole days (8 hours)
and two half days (4 hours). During the study days, subjects will lie in bed
and blood will be drawn from an infusion. No adverse events are expected from
this.
Subjects will be asked to take both Topiramate and Placebo for four weeks. We
will monitor side effects weekly.