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NCT Number: NCT04666636

Mechanisms for Activation of Beige Adipose Tissue in Humans

Mirabegron (Myrbetriq®, Astellas) is a highly specific and well-tolerated ß3 agonist marketed for overactive bladder. This trial will assess the effects of mirabegron on glucose tolerance and adipose tissue in prediabetic patients

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Key information

Conditions

PreDiabetes Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases Platelet Glycoprotein IV Deficiency Prediabetic State

Age range

35 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location status: Recruiting

Location contact

Philip Kern, MD

PRINCIPAL_INVESTIGATOR

Zach Leicht

CONTACT

[email protected]

859-218-1397

About this study

Among the many survival adaptations developed by mammals is a defense against the cold and hypothermia; one of these adaptations is the ability to uncouple oxidative phosphorylation and generate heat, rather than adenosine triphosphate (ATP), from lipid substrate in specialized tissues, and there has been much interest in exploiting this inefficient metabolism for the treatment of obesity and insulin resistance. Brown adipose tissue (BAT) protects against obesity in mice, and studies have documented cold-induced BAT in humans using positron emission tomography (PET-CT) scanning. Additional studies have demonstrated that white adipose tissue (WAT) can upregulate its thermogenic capacity and become "beige", and this beiging of SC WAT likely provides an additional defense against the cold.

Brown and beige fat can be activated by cold temperatures, or through catecholamines. The catecholamines epinephrine and norepinephrine have undesirable side effects. However, adipocytes are among the few cells that contain ß3 adrenergic receptors (ß3AR), whereas the heart is dominated by ß1 and ß2 receptors. Therefore, a drug that could target the ß3AR could activate brown/beige fat without cardiovascular side effects. Recently, there have been human studies performed and obese human subjects participants were treated with the ß3AR agonist mirabegron. This resulted in improved glucose homeostasis by increasing insulin sensitivity and insulin secretion. It was also found that mirabegron treatment of obese adults did not increase BAT or induce weight loss, but instead induced beige fat, along with increased insulin sensitivity, which was accompanied by an increase in type I fibers in skeletal muscle. Mirabegron treatment stimulated subcutaneous (SC) WAT beiging, lipolysis, and remodeling. However, unlike WAT, insulin-producing ß-cells and muscle do not express the ß3AR; therefore, it is thought that the beneficial effects of mirabegron treatment occurred by an indirect mechanism.

Currently, mirabegron (Myrbetriq®, Astellas) is a highly specific and well-tolerated ß3 agonist marketed for overactive bladder. It is hypothesized that mirabegron treatment of prediabetic subjects will improve glucose homeostasis through improved insulin sensitivity and ß-cell function, in addition to other changes in adipose tissue. Additionally, mirabegron treatment may change the plasma composition of proteins, lipids, metabolites, short-chain fatty acids, or exosomal miRNAs that are known to affect peripheral tissue function.

This trial will quantify the effects of the ß3 agonist mirabegron on glucose metabolism and adipose tissue in a placebo-controlled trial and determine some of the mechanistic underpinnings of these effects.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • BMI 27-45
  • prediabetes (A1c 5.7-6.4)
  • impaired fasting glucose or impaired glucose tolerance

Exclusion criteria

  • diabetes
  • chronic use of anti-diabetic medication
  • acute or chronic inflammatory condition
  • unstable medical condition
  • cancer
  • renal insufficiency
  • any contraindication for Mirabegron
  • BMI >45

Treatment and study plan

Placebo

Drug

Participants will take one pill (placebo) daily for the first week and two pills daily for the remaining 15 weeks.

Mirabegron

Drug

Participants will take one pill (50mg Mirabegron) daily for the first week. For week two, participants will take two pills (50mg and 25mg Mirabegron). Unless there are side effects, for the remaining 14 weeks participants will take two pills (50mg each) daily.

Other names: Myrbetriq

Mirabegron 50 MG

Drug

Participants will take one pill (50mg Mirabegron) daily between visit 2 and visit 3

Other names: Myrbetriq

Mirabegron 100 mg

Drug

participants will be given 6 weeks of mirabegron (25 mg) and will take 1 pill once per day for 4-6 weeks. Next participants will be given 6 weeks of mirabegron (50 mg) and take 1 pill once per day for 4-6 weeks. Last participants will be given 6 weeks of mirabegron (100 mg) and take 1 pill once per day for 4-6 weeks.

Other names: Myrbetriq

Primary outcomes

  1. Change in Glucose Tolerance

    Time frame: 16 weeks (at baseline and at 16 weeks)

    The standard oral glucose tolerance test (OGTT) using 75g glucose will be used to assess tolerance.

  2. Change in Body Composition

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Body composition (percent body fat) will be measured using dual-energy X-ray absorptiometry (DEXA).

  3. Change in Resting Metabolic Rate

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Resting Metabolic Rate (RMR) will be measured using indirect calorimetry.

  4. Change in Brown Adipose Tissue Activity

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Brown adipose tissue (BAT) activity will be measured using water-vest cold stimulation combined with positron emission tomography (PET-CT).

  5. Change in Peripheral Insulin Sensitivity

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Peripheral insulin sensitivity will be measured with a euglycemic clamp.

  6. Change in Insulin Secretion

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Insulin secretion will be measured with a euglycemic clamp.

  7. Change in glycohemoglobin

    Time frame: 16 weeks (at baseline and at 16 weeks)

    Hemoglobin A1c (HbA1C) will be measured from blood samples.

  8. Change in Matsuda Index for Dosing Sub Study

    Time frame: Baseline, week 6, week 12, week 18

    Comparison of change in Matsuda Index as determined by 2-h oral glucose tolerance test (OGTT). During OGTT, response to oral 75g glucose intake is determined by measuring insulin and glucose in timed samples obtained at 0, 30, 60, 90 and 120 min. Increase in scores reflect improvement in whole body insulin sensitivity.

  9. Change in bile acids/blood proteins

    Time frame: Baseline, week 1, week 2

    FGF-19 and total bile acids will be analyzed and compared across the different conditions. Plasma bile acid concentration (ng/mL) will be measured and compared across the different doses of study drug.

Study contacts

Contact information is provided by the study sponsor or research team.

Philip Kern, MD

CONTACT

[email protected]

859-218-1394

Zach Leicht

CONTACT

[email protected]

859-218-1397

Sponsors and collaborators

Lead sponsor

Philip Kern

Other

Collaborators

  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Registry information

Important dates

Study start
2020
Primary completion
2027
Study completion
2027
First posted
Dec 14, 2020
Registry last updated
Jul 7, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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