L-arginine and Brown Adipose Tissue (ArgMB)

Maastricht University Medical Centre (MUMC)

Status and phase

Unknown

Phase 3

Conditions

Adipose Tissue, Brown

Nitric Oxide

Glucose Intolerance

Treatments

Drug: L-arginine

Drug: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT02291458

NL2014-001733-86

Details and patient eligibility

About

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.

Full description

Rationale: The South Asian population originally descends from the Indian subcontinent and represents approximately 20% of the total world population. This population is facing an epidemic of type 2 diabetes, of which the underlying cause is still unknown. A high prevalence of a disadvantageous metabolic phenotype, consisting of obesity, insulin resistance and dyslipidemia, may at least in part contribute to this excess risk. 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.

Objectives: The primary objectives are: 1) to determine the effect of L-arginine on glucose uptake by brown adipose tissue and to assess whether the effect differs between South Asian and white Caucasian subjects; 2) to determine the effect of L-arginine on whole body energy expenditure and to assess whether the effect differs between South Asian and white Caucasian subjects; 3) to determine the effect of L-arginine on fat mass and to assess whether the effect differs between South Asian and white Caucasian subjects.

Study design: A randomized placebo-controlled multicenter cross-over study will be performed 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, thermoregulation will be assessed, an oral glucose tolerance will be performed and the investigators will assess NO-dependent and independent vasodilation by means of iontophoresis.

Study population: Mildly obese (BMI 25-30 kg/m2) pre-diabetic male volunteers of South Asian and white Caucasian descent aged between 35-50 years.

Intervention: The intervention will consist of administration of 9 grams of L-arginine per day in three gifts (3dd 3 gram).

Enrollment

26 estimated patients

Sex

Male

Ages

35 months to 50 years old

Volunteers

Accepts Healthy Volunteers

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)