PreDiabetes
Conditions
Keywords
beige, adipose, glucose, fat, BAT, diabetes, metabolism, DEXA
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.
Interventions
DRUGPlacebo
Participants will take one pill (placebo) daily for the first week and two pills daily for the remaining 15 weeks.
DRUGMirabegron
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.
DRUGMirabegron 50 MG
Participants will take one pill (50mg Mirabegron) daily between visit 2 and visit 3
DRUGMirabegron 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.
Sponsors
Philip Kern
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glucose Tolerance | 16 weeks (at baseline and at 16 weeks) | The standard oral glucose tolerance test (OGTT) using 75g glucose will be used to assess tolerance. |
| Change in Body Composition | 16 weeks (at baseline and at 16 weeks) | Body composition (percent body fat) will be measured using dual-energy X-ray absorptiometry (DEXA). |
| Change in Resting Metabolic Rate | 16 weeks (at baseline and at 16 weeks) | Resting Metabolic Rate (RMR) will be measured using indirect calorimetry. |
| Change in Brown Adipose Tissue Activity | 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). |
| Change in Peripheral Insulin Sensitivity | 16 weeks (at baseline and at 16 weeks) | Peripheral insulin sensitivity will be measured with a euglycemic clamp. |
| Change in Insulin Secretion | 16 weeks (at baseline and at 16 weeks) | Insulin secretion will be measured with a euglycemic clamp. |
| Change in glycohemoglobin | 16 weeks (at baseline and at 16 weeks) | Hemoglobin A1c (HbA1C) will be measured from blood samples. |
| Change in Matsuda Index for Dosing Sub Study | 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. |
| Change in bile acids/blood proteins | 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. |
Countries
United States
Contacts
CONTACTZach Leicht
CONTACTPhilip Kern, MD
PRINCIPAL_INVESTIGATORPhilip Kern, MD
University of Kentucky
Outcome results
None listed