Back to resultsRole of Allopurinol on Oxidative Stress and Mitochondrial Alterations in Skeletal Muscle of Diabetic Patients (DIAXO)
Primary Purpose
Type 2 Diabetes Mellitus
Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
2 capsules of allopurinol 150 mg daily for 3 month
2 capsules of lactose daily for 3 month
Sponsored by
About this trial
This is an interventional basic science trial for Type 2 Diabetes Mellitus focused on measuring Type 2 diabetes mellitus, oxidative stress, insulin sensitivity, insulin resistance, mitochondrial dysfunction, skeletal muscle, xanthine oxidase, allopurinol
Eligibility Criteria
Inclusion Criteria:
- BMI from 25 to 40 kg/m²
- Type 2 diabetes known for over one year but less than 10 years, treated with Oral anti-diabetic drugs or a Glucagon-like peptide-1 (GLP1-analog)
- well controlled hypertension (untreated or currently treated) with a systolic blood pressure of 95 to 140 mmHg and diastolic blood pressure of 45 to 90 mmHg and heart frequency of 40 to 100 per minute
- Recent HbA1c < 9 %
- Uricemia > 300 µmol/l
- For women : Menopausal or contraception
- Renal function as defined by glomerular filtration rate (GFR) ≥ 80 mL/min/1.73 m2
Exclusion Criteria:
- Tobacco ( more than 5 cigarettes)
- Excessive drinking
- Known pathology
- Hypersensitivity to allopurinol
- Treatment by anticoagulants, allopurinol, regular steroids or Nonsteroidal anti-inflammatory drug (NSAID), fibrate or insulin
Sites / Locations
- CRNH Rhône Alpes
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Allopurinol
Placebo
Arm Description
Allopurinol, experimental arms, type 2 diabetes subjects receive 2 capsules of allopurinol 150 mg daily for 3 month
Placebo, type 2 diabetes subjects receive 2 capsules of lactose (placebo) daily for 3 month
Outcomes
Primary Outcome Measures
muscle oxidative stress in diabetic patients
muscular protein carbonylation level (unit: reactive carbonyl derivates, arbitrary unit) by Western blot (oxyblot kit from Chemicon) and pro et antioxidant genes expression (unit: mRNA levels normalized by housekeeping gene, arbitrary ratio) by real time polymerase chain reaction (RT-PCR)
Secondary Outcome Measures
- plasmatic oxidative stress by dosing plasmaticmarkers:
Dosing plasmatic malondialdéhyde, plasmatic H2O2, protein carbonylation of plasmatic protein and urinary isoprostans, and finally antioxidants (vitamins C and E, glutathione (unit: from µM to M)
alterations in mitochondrial structure of skeletal muscle with transmission electron microscopy
Analysis of mitochondria area (in µm2) and density (in %)
mitochondrial density by measuring the ratio mitochondrial Deoxyribonucleic acid (mtDNA)/nuclear DNA by real-time polymerase chain reaction (PCR) in skeletal muscle
mitochondrial function
Expression of genes implicated in mitochondrial action (messenger Ribonucleic acid (mRNA) levels by Reverse transcription polymerase chain reaction (RT-PCR) and proteins levels by Western Blot)(unit: arbitrary ratio relative to housekeeping gene/protein).
quantification of intramuscular lipids by histology (biopsy analysis)
Staining Oil Red O evaluate the intramuscular lipid accumulation using the software ImageJ(unit: % of labelling by field).
sensitivity to insulin using a hyperinsulinemic euglycemic clamp
sensitivity to insulin will be expressed as the glucose infusion rate (GIR)/insulinemia ratio.
uricemia and xanthine oxidase activity in sera and muscles(unit: mg/l for uricemia and mU/ml for XO activity)
Plasma concentrations of uric acid will be measured before and after treatment to assess patient compliance . The reduction of xanthine oxidase activity in serum and muscle protein lysates will be measured using the kit " Amplex Red xanthine / xanthine oxidase assay kit" from Molecular Probes
Tolerance of the treatment measured by any adverse events during treatment and between each visit.
Any adverse events during treatment and between each visit.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02533648
Brief Title
Role of Allopurinol on Oxidative Stress and Mitochondrial Alterations in Skeletal Muscle of Diabetic Patients
Acronym
DIAXO
Official Title
Involvement of Reactive Oxygen Species Produced by the Xanthine Oxidase in Mitochondrial Alterations in Skeletal Muscle of Type 2 Diabetic Patients
Study Type
Interventional
2. Study Status
Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
September 16, 2011 (Actual)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
February 18, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Our recent data in mice have demonstrated a key role of xanthine oxidase in hyperglycemia-induced by Reactive oxygen species production, and a preventive role of allopurinol (inhibitor of xanthine oxidase) on the keeping of mitochondria number and structure, in skeletal muscle of diabetic mice. The investigators want to initiate a clinical trial in order to evaluate the efficacy of allopurinol on the improvement of mitochondrial alterations, oxidative capacities and insulin sensitivity, in skeletal muscle of type 2 diabetic patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus
Keywords
Type 2 diabetes mellitus, oxidative stress, insulin sensitivity, insulin resistance, mitochondrial dysfunction, skeletal muscle, xanthine oxidase, allopurinol
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Allopurinol
Arm Type
Experimental
Arm Description
Allopurinol, experimental arms, type 2 diabetes subjects receive 2 capsules of allopurinol 150 mg daily for 3 month
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo, type 2 diabetes subjects receive 2 capsules of lactose (placebo) daily for 3 month
Intervention Type
Drug
Intervention Name(s)
2 capsules of allopurinol 150 mg daily for 3 month
Intervention Description
2 capsules of allopurinol 150 mg daily for 3 month
Intervention Type
Drug
Intervention Name(s)
2 capsules of lactose daily for 3 month
Intervention Description
2 capsules of lactose daily for 3 month
Primary Outcome Measure Information:
Title
muscle oxidative stress in diabetic patients
Description
muscular protein carbonylation level (unit: reactive carbonyl derivates, arbitrary unit) by Western blot (oxyblot kit from Chemicon) and pro et antioxidant genes expression (unit: mRNA levels normalized by housekeeping gene, arbitrary ratio) by real time polymerase chain reaction (RT-PCR)
Time Frame
At 3 months of treatment
Secondary Outcome Measure Information:
Title
- plasmatic oxidative stress by dosing plasmaticmarkers:
Description
Dosing plasmatic malondialdéhyde, plasmatic H2O2, protein carbonylation of plasmatic protein and urinary isoprostans, and finally antioxidants (vitamins C and E, glutathione (unit: from µM to M)
Time Frame
At 3 months of treatment
Title
alterations in mitochondrial structure of skeletal muscle with transmission electron microscopy
Description
Analysis of mitochondria area (in µm2) and density (in %)
Time Frame
At 3 months of treatment
Title
mitochondrial density by measuring the ratio mitochondrial Deoxyribonucleic acid (mtDNA)/nuclear DNA by real-time polymerase chain reaction (PCR) in skeletal muscle
Time Frame
At 3 months of treatment
Title
mitochondrial function
Description
Expression of genes implicated in mitochondrial action (messenger Ribonucleic acid (mRNA) levels by Reverse transcription polymerase chain reaction (RT-PCR) and proteins levels by Western Blot)(unit: arbitrary ratio relative to housekeeping gene/protein).
Time Frame
At 3 months of treatment
Title
quantification of intramuscular lipids by histology (biopsy analysis)
Description
Staining Oil Red O evaluate the intramuscular lipid accumulation using the software ImageJ(unit: % of labelling by field).
Time Frame
At 3 months of treatment
Title
sensitivity to insulin using a hyperinsulinemic euglycemic clamp
Description
sensitivity to insulin will be expressed as the glucose infusion rate (GIR)/insulinemia ratio.
Time Frame
At 3 months of treatment
Title
uricemia and xanthine oxidase activity in sera and muscles(unit: mg/l for uricemia and mU/ml for XO activity)
Description
Plasma concentrations of uric acid will be measured before and after treatment to assess patient compliance . The reduction of xanthine oxidase activity in serum and muscle protein lysates will be measured using the kit " Amplex Red xanthine / xanthine oxidase assay kit" from Molecular Probes
Time Frame
At 3 months of treatment
Title
Tolerance of the treatment measured by any adverse events during treatment and between each visit.
Description
Any adverse events during treatment and between each visit.
Time Frame
during the 3 months of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
BMI from 25 to 40 kg/m²
Type 2 diabetes known for over one year but less than 10 years, treated with Oral anti-diabetic drugs or a Glucagon-like peptide-1 (GLP1-analog)
well controlled hypertension (untreated or currently treated) with a systolic blood pressure of 95 to 140 mmHg and diastolic blood pressure of 45 to 90 mmHg and heart frequency of 40 to 100 per minute
Recent HbA1c < 9 %
Uricemia > 300 µmol/l
For women : Menopausal or contraception
Renal function as defined by glomerular filtration rate (GFR) ≥ 80 mL/min/1.73 m2
Exclusion Criteria:
Tobacco ( more than 5 cigarettes)
Excessive drinking
Known pathology
Hypersensitivity to allopurinol
Treatment by anticoagulants, allopurinol, regular steroids or Nonsteroidal anti-inflammatory drug (NSAID), fibrate or insulin
Facility Information:
Facility Name
CRNH Rhône Alpes
City
Lyon
ZIP/Postal Code
69310
Country
France
12. IPD Sharing Statement
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Role of Allopurinol on Oxidative Stress and Mitochondrial Alterations in Skeletal Muscle of Diabetic Patients
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