Role of Allopurinol on Oxidative Stress and Mitochondrial Alterations in Skeletal Muscle of Diabetic Patients

Phase 3

Completed

• Conditions: Type 2 Diabetes Mellitus
• Interventions: Drug: 2 capsules of allopurinol 150 mg daily for 3 month; Drug: 2 capsules of lactose daily for 3 month

• Registration Number: NCT02533648
• Lead Sponsor: Hospices Civils de Lyon

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2011-09-16
• Study First Submitted: 2015-05-18
• Study First Submitted QC: 2015-08-24
• Study First Posted: 2015-08-27
• Primary Completion: 2016-02
• Study Completion: 2016-02-18
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-31
• Last Update Posted: 2019-11-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Allopurinol	2 capsules of allopurinol 150 mg daily for 3 month	Allopurinol, experimental arms, type 2 diabetes subjects receive 2 capsules of allopurinol 150 mg daily for 3 month
Placebo	2 capsules of lactose daily for 3 month	Placebo, type 2 diabetes subjects receive 2 capsules of lactose (placebo) daily for 3 month

Primary Outcome Measures

Name	Time	Method
muscle oxidative stress in diabetic patients	At 3 months of treatment	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

Name	Time	Method
- plasmatic oxidative stress by dosing plasmaticmarkers:	At 3 months of treatment	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)
mitochondrial density by measuring the ratio mitochondrial Deoxyribonucleic acid (mtDNA)/nuclear DNA by real-time polymerase chain reaction (PCR) in skeletal muscle	At 3 months of treatment
uricemia and xanthine oxidase activity in sera and muscles(unit: mg/l for uricemia and mU/ml for XO activity)	At 3 months of treatment	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.	during the 3 months of treatment	Any adverse events during treatment and between each visit.
mitochondrial function	At 3 months of treatment	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)	At 3 months of treatment	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	At 3 months of treatment	sensitivity to insulin will be expressed as the glucose infusion rate (GIR)/insulinemia ratio.
alterations in mitochondrial structure of skeletal muscle with transmission electron microscopy	At 3 months of treatment	Analysis of mitochondria area (in µm2) and density (in %)

Trial Locations

Locations (1)

CRNH Rhône Alpes; 🇫🇷 Lyon, France