Effect of Ursolic Acid Administration on Insulin Sensitivity and Metabolic Syndrome

Study Overview
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Brief Summary
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The metabolic syndrome is characterized by the presence of overweight/obesity, insulin resistance, hyperglycemia, dyslipidaemia and hypertension and an inflammatory state, which together increase the risk of developing cardiovascular disease (CVD) or diabetes mellitus type 2 (DM2). It is also characterized by a decreased insulin sensitivity, namely, lower ability of insulin to metabolize glucose, key in the physiopathogeny of disease process. In the search for a pharmacological agent that can attend more components of the metabolic syndrome and above all improve insulin sensitivity to effectively prevent the development of CVD and DM2, ursolic acid is a promising compound. Ursolic acid is a pentacyclic carboxylic acid present in medicinal herbs, parts of some fruits like apple peel, and plants such as rosemary. There is scientific evidence of important benefits of ursolic acid level in vitro and in vivo on insulin, metabolism of lipids and glucose, as well as on the body weight and metabolic parameters. However, the results are not clear and the mechanisms are not fully elucidate. The aim of this study is to evaluate the effect of ursolic acid on the insulin sensitivity and metabolic syndrome.

Detailed Description
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A randomized, double-blind, placebo-controlled clinical trial in 24 patients of both sexes aged between 30 and 60 years, with a diagnosis of metabolic syndrome according to the modified International Diabetes Federation (IDF) criteria, without treatment. They will be assigned randomly two groups of 12 patients, each to receive 150 mg of ursolic acid or placebo before breakfast for 12 weeks. Insulin sensitivity will be calculated by Matsuda Index with dates from glucose and insulin levels from Oral Glucose Tolerance Test; Waist circumference will be measured; triglycerides and High density lipoprotein (HDL-C) and blood pressure will be evaluated before and after intervention in both groups. Statistical analysis will be presented through measures of central tendency and dispersion, average and deviation standard for quantitative variables; frequencies and percentages for variable qualitative. Qualitative variables will be analyzed by X2, will be used for differences inter-group Mann-Whitney U Test and Wilcoxon Test for the within-groups differences. Will be considered statistical significance p ≤0.05. This protocol was approved by a local ethics committee (CEI/075/2014) and written informed consent will be obtained from all volunteers.

Official Title
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Effect of Ursolic Acid Administration on Insulin Sensitivity and Metabolic Syndrome

Conditions
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Metabolic Syndrome X

Intervention / Treatment
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* Drug: Ursolic acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed Patients both sexes Age between 30 and 60 years Metabolic Syndrome according to the IDF criteria: Waist circumference Man ≥90 cm, Woman ≥80 cm; and two of the following criteria: High density lipoprotein Man ≤40 mg/dL, Woman ≤50 mg/dL; Fasting glucose ≥100 mg/dL; Triglycerides ≥150 mg/dL; Blood pressure ≥130/85 mmHg Exclusion Criteria: Women with confirmed or suspected pregnancy Women under lactation and/or puerperium Hypersensibility to ursolic acid o calcined magnesia Physical impossibility for taking pills Known uncontrolled renal, hepatic, heart or thyroid diseased Previous treatment for the metabolic syndrome components Body Mass Index ≥39.9 kg/m2 Fasting glucose ≥126 mg/dL Triglycerides ≥500 mg/dL Total cholesterol ≥240 mg/dL Low density lipoprotein (c-LDL) ≥190 mg/dL Blood Pressure ≥140/90 mmHg

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ursolic acid<br>Ursolic acid capsules, 150 mg, once a day before breakfast during 12 weeks | Drug: Ursolic acid<br>* Ursolic acid capsules of 150 mg extracted from rosemary, once a day before breakfast<br>* Other names: Malol;|
| Placebo Comparator: Placebo<br>Calcined magnesia capsules, 150 mg, once a day before breakfast during 12 weeks | Drug: Placebo<br>* Calcined magnesia capsules of 150 mg, once a day before breakfast<br>* Other names: Calcined magnesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Insulin Sensitivity | The insulin sensitivity was calculated at baseline and at week 12. The value reported corresponds at week 12 with Matsuda index. Matsuda Index value is used to indicate insulin resistance on diabetes. Insulin sensitivity was calculated with Matsuda index [10,000 / √glucose 0' x insulin 0') (mean glucose oral glucose tolerance test (OGTT) x mean insulin OGTT)]. The entered values reflect the insulin sensitivity | Week 12 | 
| Waist Circumference | Waist circumference was evaluated at baseline and at week 12 with a flexible tape and the entered values reflect the waist circumference measure at week 12 | Week 12 | 
| Fasting Glucose | The fasting glucose levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the fasting glucose level at week 12 | Week 12 | 
| Triglycerides | The triglycerides were evaluated at baseline and week 12 with enzymatic-colorimetric techniques and the entered values reflect the triglycerides level at week 12 | Week 12 | 
| High Density Lipoprotein Cholesterol (HDL-c) | The HDL-c levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the c-HDL level at week 12 | Week 12 | 
| Systolic Blood Pressure | The systolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the systolic blood pressure at week 12 | Week 12 | 
| Diastolic Blood Pressure | The diastolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the diastolic blood pressure at week 12 | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight | The body weight was measured at baseline and week 12 with a bioimpedance balance and the entered values reflect the weight at week 12 | Week 12 | 
| Body Mass Index | The Body Mass index was calculated at baseline and at week 12 with the Quetelet index and the entered values reflect the body mass index at week 12 | Week 12 | 
| Total Cholesterol | The total cholesterol was estimated by standardized techniques at baseline and week 12 and the entered values reflect the total cholesterol level at week 12 | Week 12 | 
| Low Density Lipoproteins Cholesterol (LDL-c) | The LDL-c levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the c-LDL levels at week 12 | Week 12 | 
| Creatinine | The creatinine levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the creatinine levels at week 12 | Week 12 | 
| Uric Acid | The uric acid levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the uric acid levels at week 12 | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Syndrome, Central Obesity, Insulin Sensitivity, Ursolic Acid, Triterpenoid