Mirabegron and Brown Adipose Tissue

NCT03012113 | Unknown Phase 4 DMC

• 1 other identifier: P16.023
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Obesity and type 2 diabetes (T2D) are emerging problems worldwide. In particular South Asian individuals (representing 20% of the world population) have an increased risk of obesity and related disorders. They are at higher risk for the development of T2D as compared to white Caucasians and develop T2D at a younger age and with lower BMI. The underlying mechanisms that might explain these ethnical differences have not been clarified or understood yet. As a consequence, treatment options are limited and unfocussed, and novel specific strategies are needed. Brown adipose tissue (BAT) has recently been discovered as a major player in energy metabolism in humans. In a process known as thermogenesis, BAT takes up fatty acids (FA) and glucose from the circulation and subsequently combusts FA and glucose into heat, thereby increasing energy expenditure and improving glucose and FA metabolism. Using 18F-fluorodeoxyglucose (18F-FDG) (positron emission tomography/computed tomography) PET-CT scan analysis investigators have recently shown that South Asian individuals have less brown adipose tissue (BAT) than white Caucasians. This might suggest that they have a lower energy metabolism, which could underlie their increased predisposition for obesity and the development of T2D. Activation of BAT, for example by cold exposure, was shown to have beneficial metabolic effects in humans. Cold acclimatization can increase BAT volume, nonshivering thermogenesis, glucose uptake by BAT, as well as decrease fat mass in healthy young men. Therefore activation of BAT is considered as a novel therapeutic target in the treatment of obesity and T2D. As cold exposure is not the most desired therapeutic strategy for humans, current pre-clinical research focuses on pharmacological activation of BAT. β3-receptor agonists can be used to mimic sympathetic innervation of BAT. Our recent studies using mice with a human-like lipoprotein profile showed that treatment with a β3-receptor agonist decreased fat mass, improved dyslipidemia, increased insulin sensitivity and even attenuated the development of atherosclerosis. Likewise, the novel β3-receptor agonist (Mirabegron) has recently been shown to activate BAT in healthy young men as effectively as cold exposure. Therefore, ß3-receptor agonism would be a promising treatment option to activate BAT and enhance energy expenditure, especially for South Asians. Currently the most common way to visualize BAT in humans is by 18F-FDG PET-CT scan. However this method is both expensive and invasive, as it uses ionizing radiation. Recently, MRI, which has no radiation burden, has emerged as a novel method to visualize BAT in humans. Activation of BAT results in combustion of intracellular lipid stores, which eventually leads to a lower triglyceride (TG) content. MRI can measure TG content of tissue, and using MRI technology the activation of BAT can be quantified by the relative reduction in the TG content of BAT. The use of MRI to visualize and quantify BAT activity is a safe, cost-effective and innovative alternative to PET-CT, which has a potential to become a new gold standard in the nearby future. To investigate whether β3-receptor agonism has therapeutic potential to improve the metabolic phenotype of South Asians, investigators will perform a randomized cross-over study in which 20 healthy young men aged 18-30 years with a lean body type (BMI \<25 kg/m2) are included. Dutch South Asian individuals (n=10) and matched Dutch white Caucasian individuals (n=10) will participate in a cross-over study consisting of three different regimes. This study will investigate whether β3-receptor agonism has therapeutic potential to improve the metabolic phenotype of South Asians. The effects of a β3-receptor agonist on BAT activity in South Asians have never been studied before. Elucidating the effects of this β3-receptor agonist on BAT activity in South Asians might have major clinical implications, as it might result in the discovery of a potential novel treatment strategy to combat obesity and T2D in this especially vulnerable population.

Conditions

Obesity

Keywords

Adipose tissue; Type 2 Diabetes

Outcome Measures

Primary Outcomes (1)

• The effect of Mirabegron treatment on BAT activity measured by MRI in South Asians compared with white Caucasians.

  Brown adipose tissue activity will be measured by means of MRI

  Up to 1 year

Secondary Outcomes (4)

• Effect of Mirabegron treatment on REE between South Asian and white Caucasian individuals.

  Up to 1 year

• Mild cold exposure and Mirabegron on plasma lipoprotein profiles

  Up to 1 year

• Mirabegron treatment on plasma lipid levels between South Asian and white Caucasian individuals.

  Up to 1 year

• The effect of Mirabegron treatment on sympathetic output in South Asian and white Caucasian individuals.

  Up to 1 year

Study Arms (3)

Short term mild cooling

OTHER

Subjects will undergo a short term mild cooling protocol consisting of personalized water cooling method for approximately 2 hours.

Other: Short term mild cooling

Mirabegron

ACTIVE COMPARATOR

Subjects will receive one dosage of 200 mg Mirabegron (Astellas Pharma).

Drug: Mirabegron

Placebo

PLACEBO COMPARATOR

Subjects will receive one dosage of Placebo, which is packed and labeled to mach the active compound.

Drug: Placebo Oral Capsule

Interventions

Mirabegron DRUG

Also known as: Betmiga

Mirabegron

Short term mild cooling OTHER

Short term mild cooling

Placebo Oral Capsule DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male volunteers. 10 white Caucasians, born in the Netherlands. 10 South Asians, living in the Netherlands.
• Age: 18-30 years
• BMI ≤ 25 kg/m2

You may not qualify if:

• BMI \> 25 kg/m2
• Recent excessive weight loss or exercise
• Alcohol and/ or drugs abuse
• Smoking
• Any significant chronic disease, including diabetes
• Renal, hepatic or endocrine disease
• Heart disease or arrhythmias
• Thyroid disease or thyroid medication
• Hypertension
• Use of medication known to influence glucose and/or lipid metabolism or BAT activity (e.g. beta blockers or calcium channel blockers)
• Use of drugs that influence cardiac function or affect QT time
• Use of MAO inhibitor
• Use of systemic corticosteroids in previous six weeks
• Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
• Contraindications for undergoing an MRI scan:

Sponsors & Collaborators

• Ingrid Jazet: lead

Study Sites (1)

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

RECRUITING

Related Publications (2)

• Hoekx CA, Martinez-Tellez B, Straat ME, Bizino MB, van Eyk HJ, Lamb HJ, Smit JWA, Jazet IM, Nahon KJ, Janssen LGM, Rensen PCN, Boon MR. Circulating FGF21 is lower in South Asians compared with Europids with type 2 diabetes mellitus. Endocr Connect. 2025 Jan 6;14(2):e240362. doi: 10.1530/EC-24-0362. Print 2025 Feb 1.

  PMID: 39641307 DERIVED

• Straat ME, Jurado-Fasoli L, Ying Z, Nahon KJ, Janssen LGM, Boon MR, Grabner GF, Kooijman S, Zimmermann R, Giera M, Rensen PCN, Martinez-Tellez B. Cold exposure induces dynamic changes in circulating triacylglycerol species, which is dependent on intracellular lipolysis: A randomized cross-over trial. EBioMedicine. 2022 Dec;86:104349. doi: 10.1016/j.ebiom.2022.104349. Epub 2022 Nov 11.

  PMID: 36371986 DERIVED

MeSH Terms

Conditions

Obesity; Diabetes Mellitus, Type 2

Interventions

mirabegron

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases

Study Officials

• Ingrid Jazet, MD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ingrid Jazet, MD

CONTACT

+31 75262997; i.m.jazet@lumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: December 15, 2016
• First Posted: January 6, 2017
• Study Start: June 1, 2016
• Primary Completion: June 1, 2017
• Study Completion: September 1, 2017
• Last Updated: January 6, 2017

Record last verified: 2017-01

Locations

NL (1)