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

Type 2 Diabetes Mellitus Clinical Trial

— DIAXO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02533648
• Other study ID #: 2010.639
• Status: Completed
• Phase: Phase 3
• Start date: September 16, 2011
• Est. completion date: February 18, 2016

Study information

• Verified date: October 2019
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: February 18, 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• 2 capsules of allopurinol 150 mg daily for 3 month
2 capsules of allopurinol 150 mg daily for 3 month
• 2 capsules of lactose daily for 3 month
2 capsules of lactose daily for 3 month

Locations

Country	Name	City	State
France	CRNH Rhône Alpes	Lyon

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	At 3 months of treatment
Secondary	- 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)	At 3 months of treatment
Secondary	alterations in mitochondrial structure of skeletal muscle with transmission electron microscopy	Analysis of mitochondria area (in µm2) and density (in %)	At 3 months of treatment
Secondary	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
Secondary	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).	At 3 months of treatment
Secondary	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).	At 3 months of treatment
Secondary	sensitivity to insulin using a hyperinsulinemic euglycemic clamp	sensitivity to insulin will be expressed as the glucose infusion rate (GIR)/insulinemia ratio.	At 3 months of treatment
Secondary	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	At 3 months of treatment
Secondary	Tolerance of the treatment measured by any adverse events during treatment and between each visit.	Any adverse events during treatment and between each visit.	during the 3 months of treatment