Glucose Intolerance Clinical Trial
— ArgMBOfficial title:
The Effect of L-arginine on Brown Adipose Tissue Metabolism in South Asian and White Caucasian Subjects
The South Asian population is facing an epidemic of type 2 diabetes, of which the underlying cause is still unknown. It is currently hypothesized that an ethnic susceptibility towards a disturbed energy metabolism may underlie this disadvantageous metabolic phenotype. In line with this, the investigators recently discovered that Dutch South Asian subjects have 32% lower resting energy expenditure (REE) and 34% lower energy-combusting brown adipose tissue (BAT) compared to matched white Caucasians. Nitric oxide (NO) was recently shown to be crucial for BAT development and, interestingly, South Asians have diminished NO bioavailability. Thus, the disadvantageous metabolic phenotype in South Asians may be caused by diminished NO bioavailability resulting in lower BAT volume. Therefore, the investigators hypothesize that increasing NO generation in the body by administration of L-arginine, the precursor of NO, will improve their metabolic phenotype by increasing BAT volume, thereby increasing REE and clearance of triglycerides and glucose by BAT. To investigate this, the investigators will perform a randomized placebo-controlled multicenter cross-over study in moderately obese Dutch South Asians and matched white Caucasians. Subjects will receive L-arginine (9 gram/day) or placebo for 6 weeks, followed by a wash-out period of 4 weeks and then again 6 weeks of one of either treatments. At the end of both treatment periods, a cold-induced PET-CT scan will be performed. Furthermore, muscle and fat biopsies will be obtained and thermoregulation will be assessed.
Status | Recruiting |
Enrollment | 26 |
Est. completion date | December 2015 |
Est. primary completion date | October 2015 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Male |
Age group | 35 Months to 50 Years |
Eligibility |
Inclusion Criteria: - Caucasian or South Asian ethnicity - Age: 35-50 years - Gender: male - BMI: 25-30 kg/m2 - Plasma glucose levels 2 h after OGTT between 7.8 and 11 mM (e.g. impaired glucose tolerance) or Fasting plasma glucose levels > 5.5 mM - Good general health Exclusion Criteria: - Type 2 diabetes (determined on basis of oral glucose tolerance test (OGTT)) - BMI > 30 kg/m2 - Plasma glucose levels 2 h after OGTT < 7.8 mM - Plasma L-arginine levels < 41 or > 114 uM - Use of beta-blockers (these inhibit BAT activity) < 1 month before start of study or during study - Systolic blood pressure < 90 mmHg - Haematocrit < 0.41 or > 0.51 l/l - Haemoglobin < 8.5 or > 11.0 - Creatinine (enzymatic method) < 45 or > 100 µmol/L - ASAT > 45 U/L - ALAT > 50 U/L - Alkaline phosphatase > 125 U/L - Gamma GT > 45 U/L - Participation in an intensive weight-loss program or vigorous exercise program during the last year before the start of the study - Abuse of drugs and/or alcohol - Hyperthyroidism or hypothyroidism - Participation in earlier research or medical examinations that included PET-CT scanning - Psychologically unstable subjects (as judged by the treating medical specialist) - Subjects with mental retardation (as judged by the treating medical specialist) - Subjects with severe behaviour disorders (as judged by the treating medical specialist) |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Netherlands | Maastricht University Medical Center + | Maastricht | Limburg |
Lead Sponsor | Collaborator |
---|---|
Maastricht University Medical Center | Leiden University Medical Center |
Netherlands,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Standard uptake value of Brown adipose tissue | Glucose uptake by brown adiopse tissue will be assessed by cold-induced 18F-FDG PET-CT scan | 6 weeks | No |
Primary | Energy expenditure | Energy expenditure will be determined by means of indirect calorimetrie | 6 weeks | No |
Primary | Fat mass | Fat mass will be determined by DEXA scan | 6 weeks | No |
Secondary | Body temperatures | Skin and core body temperatures as well as gradients will be assessed by means of iButtons and ingestion of a telemetric pill, respectively. | 6 weeks | No |
Secondary | Skin perfusion and endothelial-dependent and independent vasodilation | This will be measured by means of Laser Doppler Flowmetry (LDF) and iontophoresis | 6 weeks | No |
Secondary | Skeletal muscle mitochondrial respiration/uncoupling | This will be determined in muscle biopsies by using the Oroboros 2k Oxygraph instrument present in our laboratory . | 6 weeks | No |
Secondary | Brown adipocyte recruitment and inflammation in WAT | This will be measured in subcutaneous WAT biopsies by assessing mRNA expression via real time polymerase-chain reaction (RT-PCR) and protein content by immunohistochemical stainings. | 6 weeks | No |
Secondary | Blood parameters | Venous blood will be drawn by means of a catheter placed in the antecubital vein of the underarm. By using radioimmunoassay, high performance liquid chromotogaphy (HPLC) and enzyme-linked immunosorbent assay (ELISA), blood parameters (i.e. lipids, glucose, inflammatory markers and endothelial activation markers) will be analyzed. In addition, we will perform DNA analyses from blood. | 6 weeks | No |
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