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


- candidate number3219
- NTR NumberNTR1286
- ISRCTNISRCTN wordt niet meer aangevraagd
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR21-apr-2008
- Secondary IDsP08.033 
- Public TitleThe effect of short term Topiramate treatment on insulin secretion, glucose and lipid metabolism in obese women
- Scientific TitleThe effect of short term Topiramate treatment on insulin secretion, glucose and lipid metabolism in obese women
- ACRONYMN/A
- hypothesisTopiramate treatment leads to improvement in Insulin sensitivity independent of weight reduction
- Healt Condition(s) or Problem(s) studiedObesity, Diabetes Mellitus, Insulin resistance, Topiramate
- Inclusion criteria1. Female volunteers
2. Age > 18 years and < 70 years
3. BMI > 27 kg/m2 and < 44 kg/m2
4. Fasting serum glucose (FSG) 6.1-7 mmol/L
- Exclusion criteria1. FSG >7 mmol/L
2. Psychiatric disorders and/or use of antipsychotic or antidepressants drugs at present or in the past.
3. Any significant chronic disease
4. Any significant abnormal laboratory results found during the medical screening procedure
5. Renal, hepatic or endocrine disease (including DM)
6. Use of medication known to influence glucose and/or FFA metabolism
7. Premenopausal women who do not use oral contraceptives or intrauterine device (IUD)
8. Recent weight changes or attempts to loose weight (> 3 kg weight gain or loss, within the last 3 months)
9. Difficulties to insert an intravenous catheter
10. Smoking
11. Severe claustrophobia (ventilated hood)
12. Recent blood donation (within the last 3 months)
13. Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupCrossover
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-mei-2008
- planned closingdate1-mei-2010
- Target number of participants13
- InterventionsTopiramate:
first week 25 mg od (evening)
second week 25 mg bid
third and fourth week 25 mg od (morning) + 50 mg od (evening)
- Primary outcome Glucose metabolism:
Endogenous glucose production, Ra and Rd of glucose by infusion of [6,6-2H2]glucose two-step hyperinsulinaemic euglycaemic clamp
-cell sensitivity:
Early and late response of insulin secretion (hyperglycemic clamp)
- Secondary outcome Anthropometric:
Weight, height, waist and hip circumference, Bioelectrical impedance analysis
Lipid metabolism:
Ra glycerol by infusion of [2H5]glycerol Indirect calorimetry:resting energy expenditure and RQ, glucose and lipid oxidation rates
Plasma concentrations:
Total cholesterol, HDL-C, LDL-C, Triglycerides, Glucose, insulin, glucagon, free fatty acid,
Actimety:
Resting energy expenditure, diet induced thermogenesis, active energy expenditure and total energy expenditure.
Diary:
Calorie intake, Physical activity
- TimepointsBefore and after the two four week intervention periods
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESDrs. M. Snel
- CONTACT for SCIENTIFIC QUERIESDrs. M. Snel
- Sponsor/Initiator Top Institute Pharma (TI Pharma)
- Funding
(Source(s) of Monetary or Material Support)
Top Institute Pharma (TI Pharma)
- PublicationsN/A
- Brief summaryBackground of the study:
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 -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 -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.

Objective of the study:
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 -cell sensitivity to glucose, divided in the early and late response of insulin secretion.

Study design:
Double blind randomized cross-over placebo controlled intervention study.
Study population:
13 glucose intolerant obese women
Inclusion Criteria
- Female volunteers
- Age > 18 years and < 70 years
- BMI > 27 kg/m2 and < 44 kg/m2
- Fasting serum glucose (FSG) 6.1-7 mmol/L
Exclusion criteria
- FSG >7 mmol/L
- Psychiatric disorders and/or use of antipsychotic or antidepressants drugs at present or in the past.
- Any significant chronic disease
- Any significant abnormal laboratory results found during the medical screening procedure
- Renal, hepatic or endocrine disease (including DM)
- Use of medication known to influence glucose and/or FFA metabolism
- Premenopausal women who do not use oral contraceptives or intrauterine device (IUD)
- Recent weight changes or attempts to loose weight (> 3 kg weight gain or loss, within the last 3 months)
- Difficulties to insert an intravenous catheter
- Smoking
- Severe claustrophobia (ventilated hood)
- Recent blood donation (within the last 3 months)
- Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
Intervention (if applicable):
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.

Primary study parameters/outcome of the study:
Anthropometric: Weight, height, waist and hip circumference, Bioelectrical impedance analysis
Glucose metabolism: Endogenous glucose production, Ra and Rd of glucose by infusion of [6,6-2H2]glucose two-step hyperinsulinaemic euglycaemic clamp
Lipid metabolism: Ra glycerol by infusion of [2H5]glycerol
Indirect calorimetry: resting energy expenditure and RQ, glucose and lipid oxidation rates
Plasma concentrations: Total cholesterol, HDL-C, LDL-C, Triglycerides, Glucose, insulin, glucagon, free fatty acid, total glycerol, Isotope enrichment of [6,6-2H2]glucose and [2H5]glycerol, lactate, cortisol, Growth Hormone
-cell sensitivity: Early and late response of insulin secretion (hyperglycemic clamp)
Actimety: Resting energy expenditure, diet induced thermogenesis, active energy expenditure and total energy expenditure.
Diary: Calorie intake, Physical activity
- Main changes (audit trail)
- RECORD21-apr-2008 - 28-apr-2008


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