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

Study Overview

• Status: Recruiting
• Conditions: PreDiabetes
• Intervention / Treatment: Drug: Placebo; Drug: Mirabegron

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Philip Kern, MD; Phone Number: 859-323-5821; Email: pake222@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University of Kentucky
      • Contact: Philip Kern, MD; Phone Number: 859-323-2615; Email: pake222@uky.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants in the group will receive placebo.	Drug: Placebo; Participants will take one pill (placebo) daily for the first week and two pills daily for the remaining 15 weeks.
Experimental: Mirabegron; Participants in this group will receive Mirabegron for 16 weeks.	Drug: Mirabegron; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glucose Tolerance	The standard oral glucose tolerance test (OGTT) using 75g glucose will be used to assess tolerance.	16 weeks (at baseline and at 16 weeks)
Change in Body Composition	Body composition (percent body fat) will be measured using dual-energy X-ray absorptiometry (DEXA).	16 weeks (at baseline and at 16 weeks)
Change in Resting Metabolic Rate	Resting Metabolic Rate (RMR) will be measured using indirect calorimetry.	16 weeks (at baseline and at 16 weeks)
Change in Brown Adipose Tissue Activity	Brown adipose tissue (BAT) activity will be measured using water-vest cold stimulation combined with positron emission tomography (PET-CT).	16 weeks (at baseline and at 16 weeks)
Change in Peripheral Insulin Sensitivity	Peripheral insulin sensitivity will be measured with a euglycemic clamp.	16 weeks (at baseline and at 16 weeks)
Change in Insulin Secretion	Insulin secretion will be measured with a euglycemic clamp.	16 weeks (at baseline and at 16 weeks)
Change in glycohemoglobin	Hemoglobin A1c (HbA1C) will be measured from blood samples.	16 weeks (at baseline and at 16 weeks)

Collaborators and Investigators

• Sponsor: Philip Kern
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Philip Kern, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2020
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: December 7, 2020
• First Posted (Actual): December 14, 2020

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: diabetes; metabolism; glucose; fat; BAT; DEXA; beige; adipose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Prediabetic State; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic beta-3 Receptor Agonists; Mirabegron
• Other Study ID Numbers: 60821; R01DK124626 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes