Obesity, Metabolic Syndrome, Hyperuricemia
Conditions
Keywords
Obesity, Metabolic syndrome, Hyperuricemia
Brief summary
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
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.
Interventions
DRUGRasburicase
one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Increase in Insulin-stimulated Glucose Uptake | 12 hours after reducing uric acid | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Carbonylated Protein Ratio | Before reducing uric acid | Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle |
| AFTER Rasburicase Carbonylated Protein Ratio | 12 hours after reducing uric acid | Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle |
| Baseline Plasma TRAP | Before reducing uric acid | Total Radical-Trapping Antioxidant Potential |
| The Effect of Reducing Uric Acid on Oxidative Status | 12 hours after reducing uric acid | 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. |
| Baseline Plasma FRAP | Before reducing uric acid | Ferric-Reducing Antioxidant Potential |
| AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹) | 12 hours after reducing uric acid | Ferric-Reducing Antioxidant Potential |
| AFTER Rasburicase Plasma TRAP | 12 hours after reducing uric acid | Total Radical-Trapping Antioxidant Potential |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Uric Acid 16 obese subjects (BMI 37.1±0.7 kg/m2) with uric acid \<5mg/dL | 16 |
| High Uric Acid 15 obese subjects (BMI 37.1±0.7 kg/m2) with uric acid \>6mg/dL | 15 |
| Total | 31 |
Baseline characteristics
| Characteristic | Low Uric Acid | High Uric Acid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 15 Participants | 31 Participants |
| Body mass index | 35.9 kg/m2 STANDARD_DEVIATION 3.2 | 38.3 kg/m2 STANDARD_DEVIATION 4.8 | 37.1 kg/m2 STANDARD_DEVIATION 4.1 |
| Plasma uric acid concentration | 4.5 mg/dL STANDARD_DEVIATION 0.2 | 7.1 mg/dL STANDARD_DEVIATION 1.6 | 5.7 mg/dL STANDARD_DEVIATION 1.7 |
| Region of Enrollment United States | 16 participants | 15 participants | 31 participants |
| Sex: Female, Male Female | 14 Participants | 8 Participants | 22 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 |
Outcome results
Primary
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.
Time frame: 12 hours after reducing uric acid
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Obese Subjects With Normal Uric Acid | Percent Increase in Insulin-stimulated Glucose Uptake | BASAL Insulin Sensitivity | 231 % incr. in insulin-mediated gluc. uptake | Standard Error 23 |
| Obese Subjects With Normal Uric Acid | Percent Increase in Insulin-stimulated Glucose Uptake | AFTER RASBURICASE Insulin Sensitivity | NA % incr. in insulin-mediated gluc. uptake | — |
| Obese Subjects With High Uric Acid | Percent Increase in Insulin-stimulated Glucose Uptake | BASAL Insulin Sensitivity | 162 % incr. in insulin-mediated gluc. uptake | Standard Error 24 |
| Obese Subjects With High Uric Acid | Percent Increase in Insulin-stimulated Glucose Uptake | AFTER RASBURICASE Insulin Sensitivity | 156 % incr. in insulin-mediated gluc. uptake | Standard Error 17 |
Secondary
AFTER Rasburicase Carbonylated Protein Ratio
Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle
Time frame: 12 hours after reducing uric acid
Population: Analysis only completed on subjects in the High Uric Acid group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With High Uric Acid | AFTER Rasburicase Carbonylated Protein Ratio | 1085 Ratio | Standard Error 131 |
Secondary
AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹)
Ferric-Reducing Antioxidant Potential
Time frame: 12 hours after reducing uric acid
Population: AFTER rasburicase plasma FRAP only measured in subjects with high uric acid
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With High Uric Acid | AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹) | 0.42 mmol Fe⁺² · Lˉ¹ | Standard Error 0.02 |
Secondary
AFTER Rasburicase Plasma TRAP
Total Radical-Trapping Antioxidant Potential
Time frame: 12 hours after reducing uric acid
Population: AFTER rasburicase plasma Total Radical-Trapping Antioxidant Potential (TRAP) was only measured in the subjects with high uric acid
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With High Uric Acid | AFTER Rasburicase Plasma TRAP | 0.71 mmol · Lˉ¹ | Standard Error 0.02 |
Secondary
Baseline Carbonylated Protein Ratio
Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle
Time frame: Before reducing uric acid
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With Normal Uric Acid | Baseline Carbonylated Protein Ratio | 929 Ratio | Standard Error 86 |
| Obese Subjects With High Uric Acid | Baseline Carbonylated Protein Ratio | 680 Ratio | Standard Error 56 |
Secondary
Baseline Plasma FRAP
Ferric-Reducing Antioxidant Potential
Time frame: Before reducing uric acid
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With Normal Uric Acid | Baseline Plasma FRAP | 1.03 mmol Fe⁺² · Lˉ¹ | Standard Error 0.02 |
| Obese Subjects With High Uric Acid | Baseline Plasma FRAP | 1.39 mmol Fe⁺² · Lˉ¹ | Standard Error 0.05 |
Secondary
Baseline Plasma TRAP
Total Radical-Trapping Antioxidant Potential
Time frame: Before reducing uric acid
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese Subjects With Normal Uric Acid | Baseline Plasma TRAP | 1.11 mmol · Lˉ¹ | Standard Error 0.02 |
| Obese Subjects With High Uric Acid | Baseline Plasma TRAP | 1.31 mmol · Lˉ¹ | Standard Error 0.05 |
Secondary
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.
Time frame: 12 hours after reducing uric acid
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Obese Subjects With Normal Uric Acid | The Effect of Reducing Uric Acid on Oxidative Status | BASELINE urinary isoprostanes | 1.0 ng/mg | Standard Error 0.15 |
| Obese Subjects With Normal Uric Acid | The Effect of Reducing Uric Acid on Oxidative Status | AFTER RASBURICASE isoprostanes | NA ng/mg | — |
| Obese Subjects With High Uric Acid | The Effect of Reducing Uric Acid on Oxidative Status | BASELINE urinary isoprostanes | 0.68 ng/mg | Standard Error 0.07 |
| Obese Subjects With High Uric Acid | The Effect of Reducing Uric Acid on Oxidative Status | AFTER RASBURICASE isoprostanes | 0.96 ng/mg | Standard Error 0.12 |