Investigating the Incretin Effect in Cystic Fibrosis
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Area Under Curve (AUC) of Insulin & C-peptide secretion during a matched isoglycemic clamp
研究概览
简要总结
Most Cystic fibrosis (CF) patients now commonly live well into adulthood, this means they are progressively accumulating damage to the insulin-secreting cells inside their pancreas. This explains why most adult patients have some degree of abnormal sugar regulation & rates of diabetes rise significantly with age. CF related diabetes is categorically different from other types of diabetes & its development is serious as it heralds a faster decline in lung function & a reduced life expectancy.
The hallmark of abnormal sugar handling in CF is high glucose levels after meals as the damaged pancreas responds abnormally slowly. Over 70% of the initial response of a healthy pancreas is induced, not by glucose alone, but by hormones released from the bowel known as incretins. We want to establish whether incretins are important in blood sugar handling in CF as specific drugs that enhance their effect are now available.
The study hypothesis is that the incretin system will function normally in patients with Cystic Fibrosis. To show this we will measure how much insulin secretion is dependant on incretin hormones in CF patients by comparing levels after a sugary drink test and then an intravenous glucose drip test (run at a rate that mimics the blood sugar levels obtained during the first test to make it a fair comparison ) - as incretins will only be produced in the first test when the sugar passes through the bowel any extra insulin produced will be due to these hormones. To detect resistance to the incretin hormones we will separately measure responses to direct infusions of the hormones themselves. We will explore which components of meals cause incretin hormone release from the bowel wall by measuring blood levels after different types of meals are consumed. Finally we will measure levels of the enzyme that breaks down the incretin hormones (DPP-4) to know if they are deactivated more quickly in people with CF. By describing the incretin system in CF we will considerably improve our understanding of this important condition as well as potentially highlighting new ways to treat it.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 17 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Cystic fibrosis as diagnosed by EITHER Cystic fibrosis transmembrane conductance regulator (CFTR) mutation on genotyping OR Positive sweat test (Chloride ≥60mmol/L after pilocarpine iontophoresis) AND Clinical features in keeping with a diagnosis of Cystic Fibrosis
- •Clinically stable for at least 4 weeks without inpatient or outpatient treatment for an infective exacerbation - including antibiotics (other than long-term prophylactic therapy) or steroids
排除标准
- •Active Pregnancy or <12 months Post-partum
- •Clinically unstable patients
- •Patients on long-term steroids
- •Patients with known gastroparesis or previous surgery to the gastrointestinal tract (including vagotomy)
- •History of organ transplant or planned organ transplant awaited
- •Non-CF related diabetes (e.g. Type 1 or 2 Diabetes Mellitus)
- •Active malignancy
- •Clinically significant derangements in haematological or biochemical indices
- •Clinical symptoms of malabsorption (frequent bowel motions/passing of undigested foodstuffs or steatorrhoea)
- •Known difficult venous access
- •Use of bile acid sequestrants in the previous 4 weeks
研究组 & 干预措施
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Oral Glucose Tolerance test (75g 2-hour) (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Modified Oral Glucose Tolerance Test (50g 4-hours) (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Matched isoglycemic clamp (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Hyperglycemic clamp with concurrent GLP-1 infusion (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Hyperglycemic Clamp with concurrent GIP infusion (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Hyperglycemic clamp with placebo infusion (Drug)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Liquid Meal Test (Carbohydrate-rich) (Other)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Liquid Meal Test (Fat-rich) (Other)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Liquid Meal Test (Mixed) (Other)
Cystic Fibrosis
Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions:
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich) Continuous Glucose Monitoring
干预措施: Continuous Glucose Monitoring (Device)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Oral Glucose Tolerance test (75g 2-hour) (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Modified Oral Glucose Tolerance Test (50g 4-hours) (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Matched isoglycemic clamp (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Hyperglycemic clamp with concurrent GLP-1 infusion (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Hyperglycemic Clamp with concurrent GIP infusion (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Hyperglycemic clamp with placebo infusion (Drug)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Liquid Meal Test (Carbohydrate-rich) (Other)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Liquid Meal Test (Fat-rich) (Other)
Controls
Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance.
Oral Glucose Tolerance test (75g 2-hour) Modified Oral Glucose Tolerance Test (50g 4-hours) Matched isoglycemic clamp Hyperglycemic clamp with concurrent GLP-1 infusion Hyperglycemic Clamp with concurrent GIP infusion Hyperglycemic clamp with placebo infusion Liquid Meal Test (Carbohydrate-rich)
干预措施: Liquid Meal Test (Mixed) (Other)
结局指标
主要结局
Area Under Curve (AUC) of Insulin & C-peptide secretion during a matched isoglycemic clamp
时间窗: 4 hours
Differences in Insulin \& C-peptide secretion will be measured over a 4-hour period following an oral glucose tolerance test and then separately over the same period during a matched isoglycemic glucose infusion (which will recreate the glucose values obtained during the oral glucose tolerance test). The difference in these values can be wholly attributed to the effect of incretin hormones.
Volume of intravenous glucose required to maintain a hyperglycemic clamp at 180-216mg/dL
时间窗: 3 hours
A hyperglycemic clamp uses an intravenous glucose infusion to fix blood sugar at a certain level. We will use such a technique to fix blood sugar levels at 180-216mg/dL (10-12 mmol/l) for one hour then infuse either an incretin hormone (GLP-1/GIP) or placebo (sodium chloride) for a further two hours. The excess volume of intravenous glucose required during the last two hours of the test (compared to the first) will allow us to calculate what if any effect the incretin hormones have on the pancreas in patients with Cystic Fibrosis
次要结局
- AUC incretin hormone levels (GLP-1/GIP)(4 hours)
- Serum DPP-4 levels(0 mins)