Sympathomimetics and Sympatholytics in Type 2 Diabetes: Teaching Old Drugs New Tricks
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)
研究概览
简要总结
Could sympathomimetics and sympatholytics drugs safe for the management of Type 2 Diabetes (T2D)? Based on recent evidence, we propose that pharmacological stimulation of Beta-3 adrenergic receptor (ADBR3) at higher doses of Mirabegron may be required to elicit changes in glycemia, but should be combined with Beta-1 adrenergic receptor (ADRB1) antagonists to suppress the unwanted effects on the cardiovascular system.
Together, several results establish a previously unappreciated cross-talk between Gs-coupled ADRB1 and ADRB3 in adipose tissue for the control of glucose homeostasis. Moreover, these data suggest that antagonizing ADRB1 may be a good way to significantly lower the dose of ADRB3 agonist required for glucose control.
Therefore, we believe that there are therapeutic opportunities in targeting adrenergic receptors for the treatment of T2D at least in young/middle aged people.
详细描述
In brief, participants will take part in 2 metabolic studies (A and B) performed in random order and at an interval of 7 to 14 days. Each metabolic study will last 8.5 hours with a baseline period of 2.5 hours. Participants will ingest either 200 mg of the ADRB3 agonist mirabegron (Myrbetriq, Astellas Pharma Canada) alone (study A) or in combination with 10 mg of bisoprolol, an ADRB1-antagonist (study B), at time 0.
The radioactive PET tracers (PET: positron emission tomography) used in this study are the [11C]-acetate and [18F]-FDG to estimate BAT oxidative metabolism and glucose metabolism, respectively. The perfusion of [6,6 D2]-glucose, [1,1,2,3,3-2H]-glycerol and [U-13C]-palmitate stable isotopes will also be performed in this study from time -150 min. to +300 min to examine the systemic appearance rate of glucose, glycerol and fatty acids, respectively. These studies will be almost identical (same perfusion of stable and radioactive tracers, same number of PET acquisitions) except for the drug which will be administered orally at time 0.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy subjects with normal glucose tolerance determined according to an oral glucose tolerance test;
- •BMI ≤ 30 kg/m2.
排除标准
- •Plasma triglycerides > 5.0 mmol/L at fasting;
- •More than 2 alcohol consumption per day;
- •More than 1 cigarette per day;
- •History of total cholesterol level > 7 mmol/L, of cardiovascular disease, hypertensive crisis;
- •Treatment with fibrates, thiazolidinedione, insulin,betablockers or other drugs with effects on insulin resistance or lipid metabolism (exception for antihypertensive drugs, statins or metformin);
- •Presence of a noncontrolled thyroid disease, renal or hepatic disease, history of pancreatitis, bleeding diatheses, cardiovascular disease or any other serious medical conditions;
- •History of serious gastrointestinal disorders (malabsorption, peptic ulcer, gastroesophageal reflux having required a surgery, etc.); reflux having required a surgery, etc.);
- •Presence of a pacemaker;
- •Have undergone of PET study or CT scan in the past year;
- •Chronic administration of any medication;
研究组 & 干预措施
Study A
Metabolic PET study with mirabegron
干预措施: Mirabegron (Drug)
Study B
Metabolic PET study with mirabegron and bisoprolol
干预措施: Mirabegron (Drug)
Study B
Metabolic PET study with mirabegron and bisoprolol
干预措施: Bisoprolol Fumarate (Drug)
结局指标
主要结局
Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)
时间窗: 30 minutes before and 210 minutes after drug administration
Measured with 11C-acetate using dynamic PET/CT acquisition.
BAT glucose uptake
时间窗: 240 minutes after drug administration
Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning
次要结局
- Substrate utilisation(150 minutes before and mean of time 210 and 270 minutes after drug administration (steady state).)
- Changes in pancreatic and gut hormones(150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).)
- Whole-body glucose partitioning(300 minutes after drug administration)
- Whole-body lipolysis(150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).)
- Hepatic Glucose production(150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).)
- BAT lipolysis(baseline and 300 minutes after drug administration)
研究者
Denis Blondin
Assisant professor
Université de Sherbrooke