Clinical trial NCT04666636: Mechanisms for Activation of Beige Adipose Tissue in Humans
Official title: Mechanisms for Activation of Beige Adipose Tissue in Humans
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: PreDiabetes
Keywords: beige
adipose
glucose
fat
BAT
diabetes
metabolism
DEXA
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2020-12-14
Enrollment: 65
Sex: ALL
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Glucose Tolerance
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in Body Composition
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in Resting Metabolic Rate
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in Brown Adipose Tissue Activity
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in Peripheral Insulin Sensitivity
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in Insulin Secretion
timeFrame: 16 weeks (at baseline and at 16 weeks)
measure: Change in glycohemoglobin
timeFrame: 16 weeks (at baseline and at 16 weeks)
Secondary outcomes:
Other outcomes:
Locations:
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Philip Kern, MD
role: PRINCIPAL_INVESTIGATOR
References: