The Effect of Glycemic Control and of GLP-1 Receptor Agonism on Islet GLP-1 in People
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Effect of exendin 9-39 on fasting glucagon secretion rate before and after liraglutide treatment
研究概览
简要总结
The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets. However, its regulation is at present unknown. There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell3. It is unclear if the effects of GLP1R agonism on islet GLP-1 differ in Type 1 diabetes (T1DM) compared to T2DM. This experiment will examine the effect of glycemic control ± a GLP1R agonist on islet GLP-1 in people with (T2DM) and without (T1DM) β-cells.
详细描述
The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. This supports other evidence (rodents and humans) that through the (inducible) expression of a prohormone convertase (PC-1/3), the α-cell can process proglucagon to intact GLP-15,6. 'Islet' or 'pancreatic' GLP-1 acts in a paracrine fashion to regulate insulin (basal and 1st phase) and glucagon secretion. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets.
There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell. β-cell secretion of the signaling peptide 14-3-3-Zeta is decreased by GLP1R agonism (Fig.1), stimulating α-cell production of GLP-1. This is a testable hypothesis in humans; people with type 1 diabetes (T1DM) have dysregulated glucagon secretion and evidence of islet GLP-1. It is unclear if the effects of GLP1R agonism on islet GLP-1 differ compared to T2DM. This experiment will examine the effect of glycemic control ± a GLP1R agonist on islet GLP-1 in people with (T2DM) and without (T1DM) β-cells.
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
- Single (Participant)
盲法说明
Intervention will be assigned in single-blind fashion (Placebo pens for liraglutide are unavailable). A placebo syringe created by Research Pharmacy in addition to 'masked' liraglutide pens will be used over 4-weeks
入排标准
- 年龄范围
- 25 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 1 or type 2 diabetes treated with insulin
排除标准
- •Age < 25 or > 70 years.
- •HbA1c > 10.0%
- •For female subjects: positive pregnancy test at the time of enrollment or study
- •History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
- •Prior use of GLP-1 receptor agonists in the previous year.
- •Active systemic illness or malignancy.
- •Symptomatic macrovascular or microvascular disease.
研究组 & 干预措施
Type 1 diabetes - Placebo arm
Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase
干预措施: Saline Injections (Other)
Type 1 diabetes - Liraglutide arm
Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase
干预措施: Liraglutide Pen Injector (Drug)
Type 2 diabetes - Placebo arm
Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase
干预措施: Saline Injections (Other)
Type 2 diabetes - Liraglutide arm
Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase
干预措施: Liraglutide Pen Injector (Drug)
结局指标
主要结局
Effect of exendin 9-39 on fasting glucagon secretion rate before and after liraglutide treatment
时间窗: The change in fasting glucagon secretion rate (saline vs. exendin 9-39) in the baseline study will be compared with the change in fasting glucagon secretion rate (saline vs. exendin 9-39) after 30 days of treatment with liraglutide (post-liraglutide)
Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during fasting (-30 to 0 min) of each study day.
Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia before and after liraglutide
时间窗: The change in glucagon secretion rate during hyperglycemia (saline vs. exendin 9-39) in the baseline study will be compared with the change (saline vs. exendin 9-39) after 30 days of treatment with liraglutide (post-liraglutide)
Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during hyperglycemia (150 to 180 min) of each study day.
次要结局
- Effect of exendin 9-39 on fasting glucagon secretion rate in people with type 1 diabetes vs type 2 diabetes(The change in fasting glucagon secretion (saline vs. exendin 9-39) in the baseline studies will be compared in people with type 1 diabetes vs type 2 diabetes)
- Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia in people with type 1 diabetes vs type 2 diabetes(The change in glucagon secretion during hyperglycemia (saline vs. exendin 9-39) in the baseline studies will be compared in people with type 1 diabetes vs type 2 diabetes)