Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes mellitus, oxidative stress, insulin sensitivity, insulin resistance, mitochondrial dysfunction, skeletal muscle, xanthine oxidase, allopurinol
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.
Interventions
DRUG2 capsules of allopurinol 150 mg daily for 3 month
2 capsules of allopurinol 150 mg daily for 3 month
DRUG2 capsules of lactose daily for 3 month
2 capsules of lactose daily for 3 month
Sponsors
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 %) |
| 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 | — |
| 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). |
| - 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) |
| 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. |
| 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. |
| 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). |
Countries
France
Outcome results
None listed