NCT04666636

Mechanisms for Activation of Beige Adipose Tissue in Humans

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 65 (estimated)
• Sponsor: Philip Kern · Academic / Other
• Sex: All
• Age: 35 Years – 65 Years
• Healthy volunteers: Accepted

Summary

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

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.

Conditions

• PreDiabetes

Interventions

Type	Name	Description
DRUG	Placebo	Participants will take one pill (placebo) daily for the first week and two pills daily for the remaining 15 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.
DRUG	Mirabegron 50 MG	Participants will take one pill (50mg Mirabegron) daily between visit 2 and visit 3
DRUG	Mirabegron 100 mg	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.

Timeline

• Start date: 2020-12-07
• Primary completion: 2026-06-25
• Completion: 2026-12-01
• First posted: 2020-12-14
• Last updated: 2026-02-03

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study