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Completed

NCT Number: NCT02533648

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

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.

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Key information

Conditions

Type 2 Diabetes Mellitus Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Metabolic Diseases Mitochondrial Diseases Nutritional and Metabolic Diseases

Age range

30 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

CRNH Rhône Alpes

Lyon, 69310, France

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

2 capsules of allopurinol 150 mg daily for 3 month

Drug

2 capsules of allopurinol 150 mg daily for 3 month

2 capsules of lactose daily for 3 month

Drug

2 capsules of lactose daily for 3 month

Primary outcomes

  1. muscle oxidative stress in diabetic patients

    Time frame: 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 outcomes

  1. - plasmatic oxidative stress by dosing plasmaticmarkers:

    Time frame: 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)

  2. alterations in mitochondrial structure of skeletal muscle with transmission electron microscopy

    Time frame: At 3 months of treatment

    Analysis of mitochondria area (in µm2) and density (in %)

  3. 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

  4. mitochondrial function

    Time frame: 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).

  5. quantification of intramuscular lipids by histology (biopsy analysis)

    Time frame: At 3 months of treatment

    Staining Oil Red O evaluate the intramuscular lipid accumulation using the software ImageJ(unit: % of labelling by field).

  6. sensitivity to insulin using a hyperinsulinemic euglycemic clamp

    Time frame: At 3 months of treatment

    sensitivity to insulin will be expressed as the glucose infusion rate (GIR)/insulinemia ratio.

  7. uricemia and xanthine oxidase activity in sera and muscles(unit: mg/l for uricemia and mU/ml for XO activity)

    Time frame: 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

  8. Tolerance of the treatment measured by any adverse events during treatment and between each visit.

    Time frame: during the 3 months of treatment

    Any adverse events during treatment and between each visit.

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Official study title

Involvement of Reactive Oxygen Species Produced by the Xanthine Oxidase in Mitochondrial Alterations in Skeletal Muscle of Type 2 Diabetic Patients

Acronym: DIAXO

Important dates

Study start
2011
Primary completion
2016
Study completion
2016
First posted
Aug 27, 2015
Registry last updated
Nov 1, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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