Adipose Tissue, BrownPhase 3ArgMBNCT02291458
L-arginine and Brown Adipose Tissue
A Phase 3 study testing L-arginine in people with Adipose Tissue, Brown and Glucose Intolerance, run by Maastricht University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 months to 50 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Adipose Tissue, Brown, Glucose Intolerance, Nitric Oxide
- What is being tested?
- L-arginine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 26 participants
- Where
- 1 siteNetherlands
- Study dates
- Nov 2014to Dec 2015
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 months to 50 years
- Men only
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 20Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
Maastricht University Medical Center +
Maastricht, Limburg, 6229 ER
Mariette Boon, PhD, +31648126425, m.boon@maastrichtuniversity.nl
Wouter van Marken Lichtenbelt, PhD, Tel: +31 43 388 1629, markenlichtenbelt@maastrichtuniversity.nl
About this study
Official 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.
Read the detailed 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).
- Conditions
- Adipose Tissue, Brown, Glucose Intolerance, Nitric Oxide
- Being tested
- L-arginine, Placebo
- Medical subject headings
- Glucose Intolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-arginineDrug
Also called Argimax
9 gram L-arginine / day for 6 weeks
PlaceboDrug
9 gram placebo / day for 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| L-arginine | Experimental | Subjects will receive 9 gram of L-arginine per day in three gifts (3dd 3 gram) during 6 weeks. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Standard uptake value of Brown adipose tissue
Glucose uptake by brown adiopse tissue will be assessed by cold-induced 18F-FDG PET-CT scan
Measured: 6 weeks
Energy expenditure
Energy expenditure will be determined by means of indirect calorimetrie
Measured: 6 weeks
Fat mass
Fat mass will be determined by DEXA scan
Measured: 6 weeks
Secondary outcomes (5)
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.
Measured: 6 weeks
Skin perfusion and endothelial-dependent and independent vasodilation
This will be measured by means of Laser Doppler Flowmetry (LDF) and iontophoresis
Measured: 6 weeks
Skeletal muscle mitochondrial respiration/uncoupling
This will be determined in muscle biopsies by using the Oroboros 2k Oxygraph instrument present in our laboratory .
Measured: 6 weeks
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.
Measured: 6 weeks
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.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2014 (estimated)
- Study startNov 2014
- Primary completionOct 2015 (estimated)
- Study completionDec 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Adipose Tissue, BrownStudies of the same condition, open and under way.
- More trials run by Maastricht University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 26 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Maastricht University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Leiden University Medical Center
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02291458
- Sponsor's protocol ID
- NL2014-001733-86
- Acronym
- ArgMB
- Status last verified
- Nov 2014
- First submitted
- 11 Nov 2014
- Last updated
- 14 Nov 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 31701693Boon 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.
PubMed 30377712Nahon 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.
PubMed 30070030
Study at a glance
From the registry record, last updated by the sponsor on 14 Nov 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of L-arginine on Brown Adipose Tissue Metabolism in South Asian and White Caucasian Subjects
- ClinicalTrials.gov ID
- NCT02291458
- Acronym / sponsor ID
- ArgMB / NL2014-001733-86
- Conditions
- Adipose Tissue, Brown, Glucose Intolerance, Nitric Oxide
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 26 participants (estimated)
- Lead sponsor
- Maastricht University Medical CenterUniversity, hospital or other
- Collaborators
- Leiden University Medical Center
- Study start
- Nov 2014
- Primary completion
- Oct 2015 (estimated)
- Study completion
- Dec 2015 (estimated)
- First posted
- 14 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| L-arginine | Experimental | Drug: L-arginineSubjects will receive 9 gram of L-arginine per day in three gifts (3dd 3 gram) during 6 weeks. |
| Placebo | Placebo comparator | Drug: PlaceboSubjects will receive 9 gram of placebo per day in three gifts (3 dd 3 gram) during 6 weeks. |
Who may qualify
- Ages
- 35 months to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (20 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-arginineAlso: Argimax9 gram L-arginine / day for 6 weeks | Drug | L-arginine |
| Placebo9 gram placebo / day for 6 weeks | Drug | Placebo |
Primary outcome
Standard uptake value of Brown adipose tissue
Time frame: 6 weeks
Glucose uptake by brown adiopse tissue will be assessed by cold-induced 18F-FDG PET-CT scan
Energy expenditure
Time frame: 6 weeks
Energy expenditure will be determined by means of indirect calorimetrie
Fat mass
Time frame: 6 weeks
Fat mass will be determined by DEXA scan
5 secondary outcomes
Body temperatures
Time frame: 6 weeks
Skin perfusion and endothelial-dependent and independent vasodilation
Time frame: 6 weeks
Skeletal muscle mitochondrial respiration/uncoupling
Time frame: 6 weeks
Brown adipocyte recruitment and inflammation in WAT
Time frame: 6 weeks
Blood parameters
Time frame: 6 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Nov 2014.
- Derived from this study: PubMed 31701693Janssen 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.
- Derived from this study: PubMed 30377712Boon 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.
- Derived from this study: PubMed 30070030Nahon 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maastricht University Medical Center +
Maastricht, Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing L-arginine in people with Adipose Tissue, Brown and Glucose Intolerance, run by Maastricht University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Standard uptake value of Brown adipose tissue (time frame: 6 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02291458, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2014.