UA: Effect of Reducing Uric Acid on Insulin Sensitivity and Oxidative Status

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01931527
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 76.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Metabolic Syndrome; Hyperuricemia	Drug: Rasburicase	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Effect of Plasma Uric Acid on Insulin Sensitivity, Endothelial Function and Inflammation
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Obese subjects with normal uric acid 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 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; one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min; Other Names: Elitek

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Baseline Carbonylated Protein Ratio [Before reducing uric acid]

   Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle

3. 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

4. Baseline Plasma TRAP [Before reducing uric acid]

   Total Radical-Trapping Antioxidant Potential

5. AFTER Rasburicase Plasma TRAP [12 hours after reducing uric acid]

   Total Radical-Trapping Antioxidant Potential

6. Baseline Plasma FRAP [Before reducing uric acid]

   Ferric-Reducing Antioxidant Potential

7. AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹) [12 hours after reducing uric acid]

   Ferric-Reducing Antioxidant Potential

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Samuel Klein, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01931527
• Other Study ID Numbers: 06-0509 / 201104189
• First Posted: Aug 29, 2013
• Last Update Posted: Aug 14, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Washington University School of Medicine: Obesity; Metabolic syndrome; Hyperuricemia
• Additional relevant MeSH terms: Metabolic Syndrome; Insulin Resistance; Hyperuricemia; Rasburicase

Study Results

Participant Flow

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Period Title: Overall Study
STARTED	16	15
COMPLETED	16	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Low Uric Acid	High Uric Acid	Total
Arm/Group Description	16 obese subjects (BMI 37.1±0.7 kg/m2) with uric acid <5mg/dL	15 obese subjects (BMI 37.1±0.7 kg/m2) with uric acid >6mg/dL	Total of all reporting groups
Overall Participants	16	15	31
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	15 100%	31 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	14 87.5%	8 53.3%	22 71%
Male	2 12.5%	7 46.7%	9 29%
Region of Enrollment (participants) [Number]
United States	16 100%	15 100%	31 100%
Body mass index (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	35.9 (3.2)	38.3 (4.8)	37.1 (4.1)
Plasma uric acid concentration (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	4.5 (0.2)	7.1 (1.6)	5.7 (1.7)

Outcome Measures

1. Primary Outcome

Title	Percent Increase in Insulin-stimulated Glucose Uptake
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m^2 with normal uric acid (= or < 5 mg/dL)	Subjects with a body mass index = or > 30 kg/m^2 with high uric acid (>6 mg/dL) Intervention: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	16	15
BASAL Insulin Sensitivity	231 (23)	162 (24)
AFTER RASBURICASE Insulin Sensitivity	NA (NA)	156 (17)

2. Secondary Outcome

Title	The Effect of Reducing Uric Acid on Oxidative Status
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m^2 with normal uric acid (= or < 5 mg/dL)	Subjects with a body mass index = or > 30 kg/m^2 with high uric acid (>6 mg/dL) Intervention: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	16	15
BASELINE urinary isoprostanes	1.0 (0.15)	0.68 (0.07)
AFTER RASBURICASE isoprostanes	NA (NA)	0.96 (0.12)

3. Secondary Outcome

Title	Baseline Carbonylated Protein Ratio
Description	Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle
Time Frame	Before reducing uric acid

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	16	15
Mean (Standard Error) [Ratio]	929 (86)	680 (56)

4. Secondary Outcome

Title	AFTER Rasburicase Carbonylated Protein Ratio
Description	Baseline ratio of total carbonylated proteins to the loading control protein Ran in skeletal muscle
Time Frame	12 hours after reducing uric acid

Outcome Measure Data

Analysis Population Description

Analysis only completed on subjects in the High Uric Acid group

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	0	15
Mean (Standard Error) [Ratio]	1085 (131)

5. Secondary Outcome

Title	Baseline Plasma TRAP
Description	Total Radical-Trapping Antioxidant Potential
Time Frame	Before reducing uric acid

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	16	15
Mean (Standard Error) [mmol · Lˉ¹]	1.11 (0.02)	1.31 (0.05)

6. Secondary Outcome

Title	AFTER Rasburicase Plasma TRAP
Description	Total Radical-Trapping Antioxidant Potential
Time Frame	12 hours after reducing uric acid

Outcome Measure Data

Analysis Population Description

AFTER rasburicase plasma Total Radical-Trapping Antioxidant Potential (TRAP) was only measured in the subjects with high uric acid

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	0	15
Mean (Standard Error) [mmol · Lˉ¹]	0.71 (0.02)

7. Secondary Outcome

Title	Baseline Plasma FRAP
Description	Ferric-Reducing Antioxidant Potential
Time Frame	Before reducing uric acid

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m² with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	16	15
Mean (Standard Error) [mmol Fe⁺² · Lˉ¹]	1.03 (0.02)	1.39 (0.05)

8. Secondary Outcome

Title	AFTER Rasburicase Plasma FRAP (Fe⁺² · Lˉ¹)
Description	Ferric-Reducing Antioxidant Potential
Time Frame	12 hours after reducing uric acid

Outcome Measure Data

Analysis Population Description

AFTER rasburicase plasma FRAP only measured in subjects with high uric acid

Arm/Group Title	Obese Subjects With Normal Uric Acid	Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)	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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
Measure Participants	0	15
Mean (Standard Error) [mmol Fe⁺² · Lˉ¹]	0.42 (0.02)

Adverse Events

Arm/Group Title	Obese Subjects With Normal Uric Acid		Obese Subjects With High Uric Acid
Arm/Group Description	Subjects with a body mass index = or > 30 kg/m2 with normal uric acid (= or < 5 mg/dL)		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 Rasburicase: one single infusion of rasburicase (0.19 mg/kg FFM) infused over 30 min
All Cause Mortality
	Obese Subjects With Normal Uric Acid		Obese Subjects With High Uric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Obese Subjects With Normal Uric Acid		Obese Subjects With High Uric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Obese Subjects With Normal Uric Acid		Obese Subjects With High Uric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.