The Effects of GIP and/or Xenin-25, With and Without Atropine, on Insulin Secretion in Humans With Pre-diabetes
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Insulin secretion rates during each treatment.
研究概览
简要总结
Glucose-dependent insulinotropic polypeptide (GIP) is a hormone produced in the intestine. It is released immediately after meal ingestion and increases insulin release. This, in turn, helps reduce blood glucose levels. This circuit does not work properly in humans with type 2 diabetes mellitus (T2DM).
We have previously shown that a peptide called xenin-25 can amplify the effects of GIP on insulin secretion in humans. However, xenin-25 no longer does this when humans develop T2DM. Thus, it is important to understand how xenin-25 works in humans without T2DM so we know why it does not work in humans with T2DM.
Acetylcholine is molecule produced by specific types of nerves. The effects of acetylcholine can be blocked by a drug called atropine. We have previously shown in mice that atropine prevents the ability of xenin-25 to increase the effects of GIP on insulin release. The purpose of this clinical trial is to determine if atropine also blocks the effects of xenin-25 in humans without T2DM. If it does, then impaired acetylcholine signaling may be one of the reasons humans develop T2DM and it could be possible to develop drugs that bypass this defect and increase insulin release in humans with T2DM.
详细描述
Glucose-dependent insulinotropic polypeptide (GIP) is a hormone produced in the intestine. It is released immediately after meal ingestion and increases insulin release. This, in turn, helps reduce blood glucose levels. This circuit does not work properly in humans with type 2 diabetes mellitus (T2DM).
We have previously shown that a peptide called xenin-25 can amplify the effects of GIP on insulin secretion in humans. However, xenin-25 no longer does this when humans develop T2DM. Thus, it is important to understand how xenin-25 works in humans without T2DM so we know why it does not work in humans with T2DM.
Acetylcholine is molecule produced by specific types of nerves. The effects of acetylcholine can be blocked by a drug called atropine. We have previously shown in mice that atropine prevents the ability of xenin-25 to increase the effects of GIP on insulin release. The purpose of this clinical trial is to determine if atropine also blocks the effects of xenin-25 in humans without T2DM. If it does, then impaired acetylcholine signaling may be one of the reasons humans develop T2DM and it may be possible to develop drugs that bypass this defect and increase insulin release in humans with T2DM.
To conduct this study, we will enroll humans with pre-diabetes since they respond very well to xenin-25. Potential subjects will first be checked to see if they do have pre-diabetes and also to verify that they can safely participate in the study. Once enrolled, subjects will come for 8 different visits, each separated by about 3 weeks. On each visit, the subject will be given an intravenous infusion of glucose such that blood glucose levels slowly increase over a 4 hour period. On separate occasions, the participant will also receive an infusion GIP alone, xenin-25 alone, GIP plus xenin-25, or placebo. Each of these 4 infusions will be conducted with and without an infusion of atropine (thus- the 8 visits). Blood glucose and insulin levels, as well as a host of other hormones, will be measured during each of the study visits. A comparison of the results will tell us if the effects of xenin-25 on insulin release are mediated by acetylcholine in humans.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Individuals must be able to consent for their own participation (no mental impairment affecting cognition or willingness to follow study instructions).
- •Otherwise healthy volunteers that have borderline diabetes or impaired glucose tolerance.
- •Women of childbearing potential must be currently taking/using an acceptable method of birth control. A pregnancy test will be done at the beginning of each visit. Any woman with a positive pregnancy test will be removed from the study.
- •Willingness to complete all required visits.
排除标准
- •Lacks cognitive ability to sign the consent or follow the study directions.
- •Women unwilling to use an acceptable method of contraception during the course of the study, or who are currently breast-feeding.
- •Volunteers with a history of Acute Pancreatitis.
- •Volunteers with a history of cancer (except for skin cancer).
- •Volunteer with a history of Chronic Pancreatitis and/or risk factors for chronic pancreatitis including hypertriglyceridemia, hypercalcemia and/or the presence of gallstones.
- •Volunteers with a history of gastrointestinal disorders, particularly related to gastric motility/emptying such as gastric bypass
- •Subjects taking medications known to affect glucose tolerance.
- •Significant systemic illness including heart, kidney, inflammatory, liver, or malignant disease requiring medications.
- •Narrow-angle glaucoma
- •Obstructive uropathy including benign prostatic hypertrophy, pyloric stenosis, myasthenia gravis
- •hyperthyroidism
- •angina and cardiac arrhythmias including heart block
- •Subjects unwilling to allow the use of human albumin in the preparation of the peptides.
- •Unwillingness to allow blood glucose level adjustment (if needed) with IV insulin
研究组 & 干预措施
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: Control (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: Xenin-25 without atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: GIP without atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: Placebo with atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: Xenin-25 with atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: GIP with atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: GIP plus Xenin-25 without atropine (Drug)
Pre-diabetes
Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%
干预措施: GIP plus Xenin-25 with atropine (Drug)
结局指标
主要结局
Insulin secretion rates during each treatment.
时间窗: 3 years
次要结局
- Plasma glucose levels during each treatment.(3 years)
- Plasma pancreatic polypeptide levels during each treatment.(3 years)
- Plasma glucagon levels during each treatment.(3 years)