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

October 31, 2019 updated by: Hospices Civils de Lyon

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Lyon, France, 69310
        • CRNH Rhône Alpes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 60 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Allopurinol
Allopurinol, experimental arms, type 2 diabetes subjects receive 2 capsules of allopurinol 150 mg daily for 3 month
Drug: 2 capsules of allopurinol 150 mg daily for 3 month
2 capsules of allopurinol 150 mg daily for 3 month
Placebo Comparator: Placebo
Placebo, type 2 diabetes subjects receive 2 capsules of lactose (placebo) daily for 3 month
Drug: 2 capsules of lactose daily for 3 month
2 capsules of lactose daily for 3 month

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
At 3 months of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
- 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)
At 3 months of treatment
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 %)
At 3 months of treatment
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
At 3 months of treatment
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).
At 3 months of treatment
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).
At 3 months of treatment
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.
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)
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
At 3 months of treatment
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.
during the 3 months of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospices Civils de Lyon

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 16, 2011

Primary Completion (Actual)

February 1, 2016

Study Completion (Actual)

February 18, 2016

Study Registration Dates

First Submitted

May 18, 2015

First Submitted That Met QC Criteria

August 24, 2015

First Posted (Estimate)

August 27, 2015

Study Record Updates

Last Update Posted (Actual)

November 1, 2019

Last Update Submitted That Met QC Criteria

October 31, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2010.639

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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