Type 2 DiabetesGB6NCT02811289
Pharmacological Activation of Brown Adipose Tissue Metabolism
A study testing Mirbetriq (Mirabegron), cold exposure and injection of 18FDG in people with Type 2 Diabetes, run by Université de Sherbrooke at 1 site in Canada.
Trial summary
Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Type 2 Diabetes
- What is being tested?
- Mirbetriq (Mirabegron), cold exposure and injection of 18FDG
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteCanada
- Study dates
- 5 Aug 2016to 5 Jul 2018
- Phase
- Interventional
- 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 18 to 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- BMI < 30 kg/m2
- normal glucose tolerance (2-hour post 75g OGTT glucose at < 7.8 mmol/l
- HbA1c < 5.8%
Who cannot join
- overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG;
- treatment with any drug known to affect lipid or carbohydrate metabolism;
- presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness;
- smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day;
- prior history or current fasting plasma cholesterol level > 7 mmol/l or fasting TG > 6 mmol/l.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Pharmacological or Cold-induced Activation of Brown Adipose Tissue Metabolism
Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). The mechanisms leading to excess exposure of lean tissues to fatty acids involve metabolic dysfunctions of adipose tissues and lean tissues themselves. Understanding the role of white and brown adipose tissue in this metabolic dysfunction is particularly important in predicting, preventing and treating T2D and many of its associated cardiovascular complications.
A recent breakthrough has been the demonstration that the acute oral administration of a β3 adrenergic agonist, mirabegron (200 mg), significantly increases BAT glucose uptake in healthy individuals. This suggests that mirabegron could be used as a pharmacological tool to selectively activate BAT metabolism as part of the mechanistic studies on BAT. It also suggests that mirabegron could be used pharmacologically for chronic activation of BAT in clinical trials to treat obesity and T2D. However, there are some outstanding issues regarding the use of mirabegron to activate BAT. First, there has been no direct comparison of the effect of acute cold vs. mirabegron on BAT metabolism. Second, there has been no demonstration of the effect of mirabegron on BAT oxidative metabolism since glucose uptake is only a surrogate of BAT energy expenditure. Third, acute administration of mirabegron led to significant increases in blood pressure and cardiac work, suggesting that it may also enhance energy expenditure in other organs in addition to BAT, thus confounding the role of BAT in energy homeostasis. Therefore, much remains to be known about the effect of mirabegron on BAT and cardiac energy metabolism before this drug can be used as a selective activator of BAT oxidative metabolism. The purpose of this study is to directly compare BAT oxidative metabolism under cold vs. β3-adrenergic agonist stimulation in lean healthy individuals. The investigator hypothesizes that the acute oral administration of a lower dose of mirabegron (50 mg) will result in an increase in BAT oxidative metabolism and whole-body energy expenditure, to a similar extent as cold exposure, without influencing the cardiovascular responses previously seen with the higher dose (200 mg).
Read the detailed description
The first step of the study will be direct comparison of mirabegron (protocol A) vs. cold-induced (protocol B) BAT metabolic activation using 11C-acetate to measure BAT metabolic activity. The principle of this method is measurement of tissue fast disappearance of 11C, a marker of tissue 11CO2 production. This fast tissue 11C clearance thus gives an index of tissue oxidative metabolism. Ten healthy, non obese men will undergo two identical 5h procedures in which BAT metabolism will be stimulated with a β3-agonist (mirabegron 50mg) or using cold exposure, in random order. The investigator just received approval from Health Canada to use mirabegron as part of these metabolic investigations. In brief, baseline blood samples and indirect calorimetry will be performed between time -60 to -30 min followed by i.v. injection of 11C-acetate with 30 min dynamic PET/CT scanning at room temperature in both protocol A and B. Mirabegron will be administered orally at time 0 in protocol A whereas acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B. At time 210 min (i.e. Tmax of plasma mirabegron level or 90 min after the onset of cold exposure), i.v. injection of 11C-acetate will be repeated followed by 30 min dynamic PET/CT scanning. I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning to determine BAT net glucose uptake and a whole-body PET/CT scan to determine BAT volume of metabolic activity and organ-specific glucose partitioning.
- Conditions
- Type 2 Diabetes
- Being tested
- Mirbetriq (Mirabegron), cold exposure, injection of 18FDG, injection of 11C-acetate, [3-3H]-glucose
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Mirbetriq (Mirabegron)Drug
Also called Mirabegron
50mg of Mirabegron will be administered orally at time 0 in protocol A.
cold exposureOther
Acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B
injection of 18FDGRadiation
I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning
injection of 11C-acetateRadiation
i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning
[3-3H]-glucoseRadiation
i.v. administration of 1.5 uCi/min of [3-3H]-glucose
[U-13C]-palmitateOther
i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate
2H-GlycerolOther
i.v. administration of 0.05 µmol/kg/min of 2H-glycerol
| Study group | Role | What they receive |
|---|---|---|
| Mirabegron | Experimental | Mirbetriq (Mirabegron) (50mg) will be administered orally at time 0 to activate brown adipose tissue. Receives: Drug: Mirbetriq (Mirabegron); Radiation: injection of 18FDG; Radiation: injection of 11C-acetate; Radiation: [3-3H]-glucose; Other: [U-13C]-palmitate; Other: 2H-Glycerol |
| Cold exposure | Active comparator | Cold exposure protocol using a water-conditioned cooling suit will be applied Receives: Other: cold exposure; Radiation: injection of 18FDG; Radiation: injection of 11C-acetate; Radiation: [3-3H]-glucose; Other: [U-13C]-palmitate; Other: 2H-Glycerol |
What is being measured
The primary outcome is the main question the study is designed to answer.
BAT net glucose uptake
will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.
Measured: 2 years
BAT oxidative metabolism
will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning
Measured: 2 years
BAT volume of metabolic activity
will be determined using a total body CT (16 mA) followed by a PET acquisition.
Measured: 2 years
whole body organ glucose partitioning
will be determined using a total body CT (16 mA) followed by a PET acquisition be determined using a total body CT (16 mA) followed by a PET acquisition
Measured: 2 years
Secondary outcomes (8)
lipolysis rate
will be measured using i.v. administration of [13C]-palmitate and [2H]-glycerol, using steele's non steady state equations
Measured: 2 years
Glucose appearance rate
will be determined using [3-3H]-glucose
Measured: 2 years
Energy expenditure
will be determined by indirect calorimetry from VO2 and VCO2 (Vmax29n, Sensormedics)
Measured: 2 years
Insulin sensitivity
will be determined using the HOMA-IR (based on fasting insulin and glucose levels)
Measured: 2 years
Insulin secretion rate
will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters
Measured: 2 years
β-cell function
will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin sensitivity.
Measured: 2 years
metabolite responses
will be determined using a multiplex assay system
Measured: 2 years
Electrocardiogram
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2016 (estimated)
- Study start5 Aug 2016
- Primary completion24 May 2018
- Study completion5 Jul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Type 2 DiabetesStudies of the same condition, open and under way.
- More trials run by Université de SherbrookeThe 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 N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Université de Sherbrooke
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, André Carpentier, Université de Sherbrooke
- Investigators
- André Carpentier, M.D., Principal investigator, Centre de recherche du CHUS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02811289
- Sponsor's protocol ID
- 2016-1086
- Acronym
- GB6
- Status last verified
- Aug 2018
- First submitted
- 14 Jun 2016
- Last updated
- 22 Aug 2018
- Results posted
- No
Publications
Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guerin B, Turcotte EE, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC. Human Brown Adipocyte Thermogenesis Is Driven by beta2-AR Stimulation. Cell Metab. 2020 Aug 4;32(2):287-300.e7. doi: 10.1016/j.cmet.2020.07.005.
PubMed 32755608
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacological or Cold-induced Activation of Brown Adipose Tissue Metabolism
- ClinicalTrials.gov ID
- NCT02811289
- Acronym / sponsor ID
- GB6 / 2016-1086
- Conditions
- Type 2 Diabetes
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Université de SherbrookeUniversity, hospital or other
- Study start
- 5 Aug 2016 (actual)
- Primary completion
- 24 May 2018 (actual)
- Study completion
- 5 Jul 2018 (actual)
- First posted
- 23 Jun 2016 (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.
Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). The mechanisms leading to excess exposure of lean tissues to fatty acids involve metabolic dysfunctions of adipose tissues and lean tissues themselves. Understanding the role of white and brown adipose tissue in this metabolic dysfunction is particularly important in predicting, preventing and treating T2D and many of its associated cardiovascular complications.
A recent breakthrough has been the demonstration that the acute oral administration of a β3 adrenergic agonist, mirabegron (200 mg), significantly increases BAT glucose uptake in healthy individuals. This suggests that mirabegron could be used as a pharmacological tool to selectively activate BAT metabolism as part of the mechanistic studies on BAT. It also suggests that mirabegron could be used pharmacologically for chronic activation of BAT in clinical trials to treat obesity and T2D. However, there are some outstanding issues regarding the use of mirabegron to activate BAT. First, there has been no direct comparison of the effect of acute cold vs. mirabegron on BAT metabolism. Second, there has been no demonstration of the effect of mirabegron on BAT oxidative metabolism since glucose uptake is only a surrogate of BAT energy expenditure. Third, acute administration of mirabegron led to significant increases in blood pressure and cardiac work, suggesting that it may also enhance energy expenditure in other organs in addition to BAT, thus confounding the role of BAT in energy homeostasis. Therefore, much remains to be known about the effect of mirabegron on BAT and cardiac energy metabolism before this drug can be used as a selective activator of BAT oxidative metabolism. The purpose of this study is to directly compare BAT oxidative metabolism under cold vs. β3-adrenergic agonist stimulation in lean healthy individuals. The investigator hypothesizes that the acute oral administration of a lower dose of mirabegron (50 mg) will result in an increase in BAT oxidative metabolism and whole-body energy expenditure, to a similar extent as cold exposure, without influencing the cardiovascular responses previously seen with the higher dose (200 mg).
Detailed description
The first step of the study will be direct comparison of mirabegron (protocol A) vs. cold-induced (protocol B) BAT metabolic activation using 11C-acetate to measure BAT metabolic activity. The principle of this method is measurement of tissue fast disappearance of 11C, a marker of tissue 11CO2 production. This fast tissue 11C clearance thus gives an index of tissue oxidative metabolism. Ten healthy, non obese men will undergo two identical 5h procedures in which BAT metabolism will be stimulated with a β3-agonist (mirabegron 50mg) or using cold exposure, in random order. The investigator just received approval from Health Canada to use mirabegron as part of these metabolic investigations. In brief, baseline blood samples and indirect calorimetry will be performed between time -60 to -30 min followed by i.v. injection of 11C-acetate with 30 min dynamic PET/CT scanning at room temperature in both protocol A and B. Mirabegron will be administered orally at time 0 in protocol A whereas acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B. At time 210 min (i.e. Tmax of plasma mirabegron level or 90 min after the onset of cold exposure), i.v. injection of 11C-acetate will be repeated followed by 30 min dynamic PET/CT scanning. I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning to determine BAT net glucose uptake and a whole-body PET/CT scan to determine BAT volume of metabolic activity and organ-specific glucose partitioning.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mirabegron | Experimental | Drug: Mirbetriq (Mirabegron), Radiation: injection of 18FDG, Radiation: injection of 11C-acetate, Radiation: [3-3H]-glucose, Other: [U-13C]-palmitate, Other: 2H-GlycerolMirbetriq (Mirabegron) (50mg) will be administered orally at time 0 to activate brown adipose tissue. |
| Cold exposure | Active comparator | Other: cold exposure, Radiation: injection of 18FDG, Radiation: injection of 11C-acetate, Radiation: [3-3H]-glucose, Other: [U-13C]-palmitate, Other: 2H-GlycerolCold exposure protocol using a water-conditioned cooling suit will be applied |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- BMI < 30 kg/m2
- normal glucose tolerance (2-hour post 75g OGTT glucose at < 7.8 mmol/l
- HbA1c < 5.8%
Key exclusion criteria (5 listed)
- overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG;
- treatment with any drug known to affect lipid or carbohydrate metabolism;
- presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness;
- smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day;
- prior history or current fasting plasma cholesterol level > 7 mmol/l or fasting TG > 6 mmol/l.
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 |
|---|---|---|
| Mirbetriq (Mirabegron)Also: Mirabegron50mg of Mirabegron will be administered orally at time 0 in protocol A. | Drug | Mirabegron |
| cold exposureAcute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B | Other | Cold exposure |
| injection of 18FDGI.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning | Radiation | Cold exposure, Mirabegron |
| injection of 11C-acetatei.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning | Radiation | Cold exposure, Mirabegron |
| [3-3H]-glucosei.v. administration of 1.5 uCi/min of [3-3H]-glucose | Radiation | Cold exposure, Mirabegron |
| [U-13C]-palmitatei.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate | Other | Cold exposure, Mirabegron |
| 2H-Glyceroli.v. administration of 0.05 µmol/kg/min of 2H-glycerol | Other | Cold exposure, Mirabegron |
Primary outcome
BAT net glucose uptake
Time frame: 2 years
will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.
BAT oxidative metabolism
Time frame: 2 years
will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning
BAT volume of metabolic activity
Time frame: 2 years
will be determined using a total body CT (16 mA) followed by a PET acquisition.
whole body organ glucose partitioning
Time frame: 2 years
will be determined using a total body CT (16 mA) followed by a PET acquisition be determined using a total body CT (16 mA) followed by a PET acquisition
8 secondary outcomes
lipolysis rate
Time frame: 2 years
Glucose appearance rate
Time frame: 2 years
Energy expenditure
Time frame: 2 years
Insulin sensitivity
Time frame: 2 years
Insulin secretion rate
Time frame: 2 years
β-cell function
Time frame: 2 years
metabolite responses
Time frame: 2 years
Electrocardiogram
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2018.
- Derived from this study: PubMed 32755608Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guerin B, Turcotte EE, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC. Human Brown Adipocyte Thermogenesis Is Driven by beta2-AR Stimulation. Cell Metab. 2020 Aug 4;32(2):287-300.e7. doi: 10.1016/j.cmet.2020.07.005.
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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.
André Carpentier, M.D. principal investigator
Centre de recherche du CHUS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Mirbetriq (Mirabegron), cold exposure and injection of 18FDG in people with Type 2 Diabetes, run by Université de Sherbrooke at 1 site in Canada.
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 3 inclusion and 5 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: finished, as of the sponsor's last update on 22 Aug 2018. 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 Canada. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
BAT net glucose uptake (time frame: 2 years). The study lists 4 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 NCT02811289, which also lists 1 linked publication.
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 22 Aug 2018.