L-arginine and Brown Adipose Tissue

NCT02291458 | Unknown Phase 3 DMC

• 1 other identifier: NL2014-001733-86
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Adipose Tissue, Brown; Glucose Intolerance; Nitric Oxide

Outcome Measures

Primary Outcomes (3)

• 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

• Energy expenditure

  Energy expenditure will be determined by means of indirect calorimetrie

  6 weeks

• Fat mass

  Fat mass will be determined by DEXA scan

  6 weeks

Secondary Outcomes (5)

• Body temperatures

  6 weeks

• Skin perfusion and endothelial-dependent and independent vasodilation

  6 weeks

• Skeletal muscle mitochondrial respiration/uncoupling

  6 weeks

• Brown adipocyte recruitment and inflammation in WAT

  6 weeks

• Blood parameters

  6 weeks

Study Arms (2)

L-arginine

EXPERIMENTAL

Subjects will receive 9 gram of L-arginine per day in three gifts (3dd 3 gram) during 6 weeks.

Drug: L-arginine

Placebo

PLACEBO COMPARATOR

Subjects will receive 9 gram of placebo per day in three gifts (3 dd 3 gram) during 6 weeks.

Drug: Placebo

Interventions

L-arginine DRUG

9 gram L-arginine / day for 6 weeks

Also known as: Argimax

L-arginine

Placebo DRUG

9 gram placebo / day for 6 weeks

Placebo

Eligibility Criteria

• Age: 35 Months - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• Leiden University Medical Center: collaborator

Study Sites (1)

Maastricht University Medical Center +

Maastricht, Limburg, 6229 ER, Netherlands

RECRUITING

Related Publications (3)

• Janssen LGM, Van Dam AD, Hanssen MJW, Kooijman S, Nahon KJ, Reinders H, Jazet IM, Van Marken Lichtenbelt WD, Rensen PCN, Appelman-Dijkstra NM, Boon MR. Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men. Diabetes Metab J. 2020 Apr;44(2):326-335. doi: 10.4093/dmj.2019.0031. Epub 2019 Oct 31.

  PMID: 31701693 DERIVED

• Boon MR, Hanssen MJW, Brans B, Hulsman CJM, Hoeks J, Nahon KJ, Bakker C, van Klinken JB, Havekes B, Schaart G, Jazet IM, Rensen PCN, van Marken Lichtenbelt WD. Effect of L-arginine on energy metabolism, skeletal muscle and brown adipose tissue in South Asian and Europid prediabetic men: a randomised double-blinded crossover study. Diabetologia. 2019 Jan;62(1):112-122. doi: 10.1007/s00125-018-4752-6. Epub 2018 Oct 30.

  PMID: 30377712 DERIVED

• Nahon KJ, Kantae V, den Haan R, Hanssen MJW, Harms AC, van der Stelt M, Hankemeier T, Jazet IM, van Marken Lichtenbelt WD, Rensen PCN, Boon MR. Gene Expression of Endocannabinoid System Components in Skeletal Muscle and Adipose Tissue of South Asians and White Caucasians with Overweight. Obesity (Silver Spring). 2018 Aug;26(8):1332-1337. doi: 10.1002/oby.22245. Epub 2018 Aug 1.

  PMID: 30070030 DERIVED

MeSH Terms

Conditions

Glucose Intolerance

Interventions

Arginine

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2014
• First Posted: November 14, 2014
• Study Start: November 1, 2014
• Primary Completion: October 1, 2015
• Study Completion: December 1, 2015
• Last Updated: November 14, 2014

Record last verified: 2014-11

Locations

NL (1)