L-arginine and Brown Adipose Tissue

Overview

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.

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).