Mechanisms for Activation of Beige Adipose Tissue in Humans
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- Change in Insulin Secretion
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 35 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •BMI 27-45
- •prediabetes (A1c 5.7-6.4)
- •impaired fasting glucose or impaired glucose tolerance
排除标准
- •chronic use of anti-diabetic medication
- •acute or chronic inflammatory condition
- •unstable medical condition
- •renal insufficiency
- •any contraindication for Mirabegron
研究组 & 干预措施
Mirabegron
Participants in this group will receive Mirabegron for 16 weeks.
干预措施: Mirabegron (Drug)
Sub-Study: Mirabegron and the acute response to food
This sub-study will involve the recruiting of the same subjects who are eligible for this study as described above. Subjects will report to the CCTS fasting on 3 separate days. On each visit, the subject will have 5 blood draws and each blood draw will be about 8 ml, for a total of 40 ml of blood at each visit. Visit 1 will involve the participant consuming a standardized meal. At visit 2, participants will take 50mg of Mirabegron. And visit 3 will involve the participant consuming the same meal as visit 1 and also taking 50 mg of mirabegron.
干预措施: Mirabegron 50 MG (Drug)
Placebo
Participants in the group will receive placebo.
干预措施: Placebo (Drug)
Sub-Study: Mirabegron dosing and Oral Glucose Tolerance Tests (Optional)
Studies have found that larger doses of mirabegron do not elicit the same improvements in insulin sensitivity. Therefore, we aim to perform a dose-response study to gain an improved understanding of mirabegron dosing and changes in insulin sensitivity.
This sub-study will have 4 total visits. visit 1 is a baseline oral glucose tolerance test. At the end of visit 1, participants will be given 6 weeks of mirabegron (25 mg) and will take 1 pill once per day for 4-6 weeks leading up to visit 2. Visit 2 will also be a standard oral glucose tolerance test. At the end of visit 2, participants will be given 6 weeks of mirabegron (50 mg) and take 1 pill once per day for 4-6 weeks leading up to visit 3. Visit 3 will also be a standard oral glucose tolerance test. At the end of visit 3, participants will be given 6 weeks of mirabegron (10 mg) and take 1 pill once per day for 4-6 weeks. Visit 4 will be the final visit and will also be a standard oral glucose tolerance test.
干预措施: Mirabegron 100 mg (Drug)
结局指标
主要结局
Change in Insulin Secretion
时间窗: 16 weeks (at baseline and at 16 weeks)
Insulin secretion will be measured with a euglycemic clamp.
Change in glycohemoglobin
时间窗: 16 weeks (at baseline and at 16 weeks)
Hemoglobin A1c (HbA1C) will be measured from blood samples.
Change in Glucose Tolerance
时间窗: 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
时间窗: 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
时间窗: 16 weeks (at baseline and at 16 weeks)
Resting Metabolic Rate (RMR) will be measured using indirect calorimetry.
Change in Brown Adipose Tissue Activity
时间窗: 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
时间窗: 16 weeks (at baseline and at 16 weeks)
Peripheral insulin sensitivity will be measured with a euglycemic clamp.
Change in Brown Adipose Tissue Activity
时间窗: 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 Glucose Tolerance
时间窗: 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
时间窗: 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
时间窗: 16 weeks (at baseline and at 16 weeks)
Resting Metabolic Rate (RMR) will be measured using indirect calorimetry.
Change in Peripheral Insulin Sensitivity
时间窗: 16 weeks (at baseline and at 16 weeks)
Peripheral insulin sensitivity will be measured with a euglycemic clamp.
Change in Insulin Secretion
时间窗: 16 weeks (at baseline and at 16 weeks)
Insulin secretion will be measured with a euglycemic clamp.
Change in glycohemoglobin
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
未报告次要终点
研究者
Philip Kern
Professor
University of Kentucky