Effect of Reducing Uric Acid on Insulin Sensitivity and Oxidative Status

Study Overview
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Brief Summary
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The purpose of this study is to learn more about what is the effect of uric acid on oxidative stress and on the way the body metabolizes sugar in obese people. Understanding this may lead to better diseases such as diabetes.

Detailed Description
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It has been hypothesized that oxidative stress is involved in the pathogenesis of insulin resistance associated with obesity. Circulating uric acid (UA) is the body's major endogenous plasma antioxidant. Therefore, the investigators evaluated whether alterations in serum UA concentration affect: 1) systemic and skeletal muscle oxidative stress, 2) total antioxidant capacity, and 4) skeletal muscle insulin sensitivity during a hyperinsulinemic-euglycemic clamp.

Official Title
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Effect of Plasma Uric Acid on Insulin Sensitivity, Endothelial Function and Inflammation

Conditions
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Obesity, Metabolic Syndrome, Hyperuricemia

Intervention / Treatment
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* Drug: Rasburicase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: obese (BMI 30-45 kg/m²); serum UA concentration either ≥5 mg/dL or ≤4.0 mg/dL (297 µmol/L)], Exclusion Criteria: renal dysfunction (serum creatinine >1.5 mg/dL); pregnancy or lactating; take urate-lowering agents, thiazide diuretics, prednisone or medications containing aspirin or other salicylates; history of xanthinuria, type 2 diabetes or other significant organ system dysfunction; have G6PD deficiency; use hormone-replacement or oral-contraceptive therapy; smoke tobacco; anemic (Hb <10 g/dl)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Obese subjects with normal uric acid<br>Subjects with a body mass index = or > 30 kg/m² with normal uric acid (= or < 5 mg/dL) | |
| Experimental: Obese subjects with high uric acid<br>Subjects with a body mass index = or > 30 kg/m² with high uric acid (>6 mg/dL) Intervention: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min | Drug: Rasburicase<br>* one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min<br>* Other names: Elitek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Increase in Insulin-stimulated Glucose Uptake | Uric acid will be reduced to 0 with a 30 minute infusion of a uricase (Elitek, Sanofi-Aventis). A hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope glucose tracer infusion will be used to measure percent increase in insulin-stimulated glucose uptake in obese subjects with high uric acid before and after uric acid reduction. | 12 hours after reducing uric acid | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Reducing Uric Acid on Oxidative Status | Uric acid will be reduced to 0 with a 30 minute infusion of a uricase (Elitek, Sanofi-Aventis). Systemic (urinary isoprostanes) and skeletal muscle (carbonylated protein ratio) oxidative stress and total antioxidant capacity (plasma TRAP and FRAP) will be measured in obese subjects with high uric acid before and after uric acid reduction. Levels of isoprostanes were normalized to urinary creatinine and reported at ng/mg. | 12 hours after reducing uric acid | 
| Baseline Carbonylated Protein Ratio | Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle | Before reducing uric acid | 
| AFTER Rasburicase Carbonylated Protein Ratio | Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle | 12 hours after reducing uric acid | 
| Baseline Plasma TRAP | Total Radical-Trapping Antioxidant Potential | Before reducing uric acid | 
| AFTER Rasburicase Plasma TRAP | Total Radical-Trapping Antioxidant Potential | 12 hours after reducing uric acid | 
| Baseline Plasma FRAP | Ferric-Reducing Antioxidant Potential | Before reducing uric acid | 
| AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹) | Ferric-Reducing Antioxidant Potential | 12 hours after reducing uric acid | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Metabolic syndrome, Hyperuricemia